NM_016042.4:c.395A>C

Variant names:

• chr9-37783993-T-G
• rs141138948
• NM_016042.4:c.395A>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_Moderate PP5_Very_Strong

The NM_016042.4(EXOSC3):​c.395A>C​(p.Asp132Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000706 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D132D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (0 hom.)
• Consequence: EXOSC3 NM_016042.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:41
• Conservation: PhyloP100: 7.92
• Publications: 50 publications found

Genes affected

EXOSC3 (HGNC:17944): (exosome component 3) This gene encodes a non-catalytic component of the human exosome, a complex with 3'-5' exoribonuclease activity that plays a role in numerous RNA processing and degradation activities. Related pseudogenes of this gene are found on chromosome 19 and 21. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2012]

EXOSC3 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Illumina
• pontocerebellar hypoplasia type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000255872 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant 9-37783993-T-G is Pathogenic according to our data. Variant chr9-37783993-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 31688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOSC3	NM_016042.4	c.395A>C	p.Asp132Ala	missense_variant	Exon 2 of 4	ENST00000327304.10	NP_057126.2
EXOSC3	NM_001002269.2	c.395A>C	p.Asp132Ala	missense_variant	Exon 2 of 3		NP_001002269.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOSC3	ENST00000327304.10	c.395A>C	p.Asp132Ala	missense_variant	Exon 2 of 4	1	NM_016042.4	ENSP00000323046.4
ENSG00000255872	ENST00000540557.1	n.*831A>C		non_coding_transcript_exon_variant	Exon 9 of 12	5		ENSP00000457548.1
ENSG00000255872	ENST00000540557.1	n.*831A>C		3_prime_UTR_variant	Exon 9 of 12	5		ENSP00000457548.1

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000406 AC: 102 AN: 251366 AF XY: 0.000397

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000748

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000729 AC: 1066 AN: 1461748 Hom.: 0 Cov.: 31 AF XY: 0.000747 AC XY: 543 AN XY: 727174

African (AFR) AF: 0.000120 AC: 4 AN: 33472

American (AMR) AF: 0.000246 AC: 11 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86248

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.000904 AC: 1005 AN: 1111954

Other (OTH) AF: 0.000563 AC: 34 AN: 60392

GnomAD4 genome AF: 0.000480 AC: 73 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74356

African (AFR) AF: 0.000193 AC: 8 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000911 AC: 62 AN: 68046

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000156 Hom.: 0

Bravo AF: 0.000416

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000321 AC: 39

EpiCase AF: 0.000873

EpiControl AF: 0.000830

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:41

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pontocerebellar hypoplasia type 1B Pathogenic:26

Jan 04, 2021

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 22, 2014

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Sep 30, 2020

Institute of Human Genetics, Cologne University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.395A>C;p.(Asp132Ala) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 31688; PMID: 23975261; 28687512; 30986545; 23564332; 23564332; 29656927; 24524299; 27146152; 24970098; 23883322; 22544365) -. PS4.The variant is present at low allele frequencies population databases (rs141138948– gnomAD 0.004796%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Asp132Ala) was detected in trans with a pathogenic variant (PMID: 23975261; 28687512; 23564332; 23564332; 24524299; 24524299; 27146152) -PM3_very strong The variant co-segregated with disease in multiple affected family members (PMID: 23975261; 30986545; 23564332; 27146152) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Feb 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 14, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM3_VSTR,PS3_SUP,PM2_SUP,PP3 -

Apr 05, 2016

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 132 of the EXOSC3 protein (p.Asp132Ala). This variant is present in population databases (rs141138948, gnomAD 0.07%). This missense change has been observed in individuals with pontocerebellar hypoplasia (PMID: 22544365, 23975261, 24524299, 25533962). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31688). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt EXOSC3 protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on EXOSC3 function (PMID: 22544365, 27777260, 28687512). For these reasons, this variant has been classified as Pathogenic. -

Jun 30, 2020

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.395A>C, p.Asp132Ala missense variant identified in the EXOSC3 gene has been reported previously in multiple unrelated individuals with pontocerebellar hypoplasia type 1 [PMID: 22544365; PMID: 25149867; PMID: 23975261; PMID: 24524299; PMID: 29656927]. This variant has a frequency of 0.05% (69 heterozygous out of 143304 alleles) in gnomAD database which is low enough to be consistent with a recessive carrier frequency. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the available evidence, the variant c.395A>C, p.Asp132Ala in the EXOSC3 gene is classified as pathogenic. -

Oct 25, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3_VS, PP1, PP3, PM2 -

Mar 10, 2021

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Lifecell International Pvt. Ltd

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A Homozygote Missense variant c.395A>C in Exon 2 of the EXOSC3 gene that results in the amino acid substitution p.Asp132Ala was identified. The observed variant has a minor allele frequency of 0.00041/0.00041% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 31688 as of 2022-12-24). The c.395A>C, p.Asp132Ala missense variant identified in the EXOSC3 gene has been reported previously in multiple unrelated individuals with pontocerebellar hypoplasia type 1 (Wan, Jijun et al., 2012). Functionally, the variant causes dysfunctional exosome complex (Schottmann, Gudrun et al., 2017). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with pontocerebellar hypoplasia, type 1B (MIM#614678). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to alanine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (115 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (9 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated RNA binding S1 domain (PMID: 22544365). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic and likely pathogenic, and has been reported in many homozygous and compound heterozygous patients with pontocerebellar hypoplasia (ClinVar, PMID: 22544365). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

-

Institute of Human Genetics, University Hospital of Duesseldorf

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 07, 2019

Clinical Genetics, University of Leipzig

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 25, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4 moderate, PM2 moderate, PM3 very strong, PP1 strong, PP3 supporting -

Dec 12, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The EXOSC3 c.395A>C p.(Asp132Ala) missense variant has been identified in individuals with a phenotype consistent with pontocerebellar hypoplasia (Wan et al. 2012; Biancheri et al. 2013; Rudnik-Schöneborn et al. 2013; Zanni et al. 2013; Eggens et al. 2014; Schottman et al. 2017). At least one study indicated that a milder phenotype was observed when the variant was present in a homozygous state, but was more severe in individuals carrying the variant in a compound heterozygous state (Rudnik-Schöneborn et al. 2013). The highest frequency of this allele in the Genome Aggregation Database is 0.000904 in the European (non-Finnish) population (version 2.1.1). Morpholino knockdown of exosc3 in zebrafish embryos recapitulated the human phenotype; rescue of the abnormal phenotype was less effective with variant protein than wildtype protein (Wan et al. 2012). Functional studies in patient fibroblasts showed that the variant protein was largely retained in the cytosol and Golgi system compared with the speckled distribution in the nucleus of control cells (Schottman et al. 2017). Additionally, structural models in yeast Rrp40 demonstrate that the p.Asp132Ala variant impairs formation of a loop in the S1 domain, which is essential for interfacing with EXOSC5 and EXOSC9 (Fasken et al. 2017). Based on the collective evidence, the c.395A>C p.(Asp132Ala)variant is classified as pathogenic for pontocerebellar hypoplasia. -

-

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This mutation has been previously reported as disease-causing and was found once in our laboratory homozygous in a 7-year-old male with severe intellectual disability, hypotonia, progressive dystonia, dysmorphism, microcephaly, progressive contractures, failure to thrive, and a similarly affected sibling -

May 27, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 26, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The homozygous p.Asp132Ala variant in EXOSC3 was identified by our study in one individual with pontocerebellar hypoplasia. The p.Asp132Ala variant in EXOSC3 has been reported in 28 individuals with pontocerebellar hypoplasia, segregated with disease in 28 individuals with pontocerebellar hypoplasia with a variety of ethnic backgrounds (including Cuban, Canadian, European, Turkish, American, and Australian) and segregated with disease in 4 affected relatives from 2 families (PMID: 29656927, 22544365, 23975261, 24524299), and has been identified in 0.07279% (94/129130) of European (non-Finnish) chromosome by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs141138948). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservational analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with 8 variants (including 3 loss of function variants) and in individuals with pontocerebellar hypoplasia increases the likelihood that the p.Asp132Ala variant is pathogenic (PMID: 23975261, 22544365, 24524299; Variation ID: 129024, 31690, 488793, 31689). In summary, this variant meets criteria to be classified as pathogenic for pontocerebellar hypoplasia in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with reported pathogenic EXOSC3 variants in individuals with the disease. ACMG/AMP Criteria applied: PM2, PP3, PM3_VeryStrong, PP1_Moderate (Richards 2015). -

Mar 08, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.041%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.91 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.85 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000031688 /PMID: 22544365 /3billion dataset). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 22544365, 24524299). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 22544365). A different missense change at the same codon (p.Asp132Tyr) has been reported to be associated with EXOSC3 related disorder (PMID: 34582790). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:9

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 26, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23284067, 8147499, 22544365, 24524299, 23564332, 27777260, 25533962, 28687512, 11110791, 25326635, 30950035, 31692161, 30986545, 23975261, 31130284, 31980526, 33462000, 32645003, 31589614, 33163565, 33144682) -

Jun 18, 2014

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EXOSC3: PM3:Very Strong, PP1:Strong, PM2 -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 08, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2021

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital pontocerebellar hypoplasia type 1 Pathogenic:1

Feb 08, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

EXOSC3-related disorder Pathogenic:1

Apr 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The EXOSC3 c.395A>C variant is predicted to result in the amino acid substitution p.Asp132Ala. This variant has been reported as causative for pontocerebellar hypoplasia in both the homozygous and compound heterozygous states (Wan et al. 2012. PubMed ID: 22544365; Eggens et al. 2014. PubMed ID: 24524299; Fasken et al. 2017. PubMed ID: 27777260). This variant is reported in 0.073% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Inborn genetic diseases Pathogenic:1

Aug 03, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.395A>C (p.D132A) alteration is located in exon 2 (coding exon 2) of the EXOSC3 gene. This alteration results from an A to C substitution at nucleotide position 395, causing the aspartic acid (D) at amino acid position 132 to be replaced by an alanine (A). Based on data from the Genome Aggregation Database (gnomAD), the EXOSC3 c.395A>C alteration was observed in 0.04% (115/282766) of total alleles studied, with a frequency of 0.07% (94/129130) in the European (non-Finnish) subpopulation. The c.395A>C (p.D132A) alteration is the most common cause of EXOSC3-related pontocerebellar hypoplasia. This mutation has been reported in multiple affected individuals in the homozygous or compound heterozygous state (Wan, 2012; Biancheri, 2013; Eggens, 2014). The p.D132A alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

See cases Pathogenic:1

Dec 21, 2022

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypotonia Pathogenic:1

Sep 04, 2016

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Abnormality of the nervous system Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.6	M;M
PhyloP100		7.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.4	D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.99	D;.
Vest4		0.98
MVP		0.96
MPC		0.65
ClinPred		0.73	D
GERP RS		5.3
Varity_R		0.93
gMVP		0.80
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs141138948; hg19: chr9-37783990;