rs62642937

Positions:

• chr12-102843706-G-A

Variant summary

Our verdict is Pathogenic. Variant got 9 ACMG points: 9P and 0B. PM3 PS3 PP4_Moderate PP3

This summary comes from the ClinGen Evidence Repository: The c.1139C>T (p.Thr380Met) variant in PAH has been reported in 1 patient with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID:8268925). This variant has 28% enzyme activity (PS3; PMID:27620137). This variant was detected in trans with multiple known pathogenic variants: R408W, R261Q, I65T, F299C (PM3_Very-strong; PMID:7981714). Computational prediction tools and conservation analysis suggest that the c.1139C>T variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3_Very-strong LINK:https://erepo.genome.network/evrepo/ui/classification/CA114369/MONDO:0009861/006

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (1 hom.)
• Consequence: PAH ENST00000553106.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:30 U:2 O:1
• Conservation: PhyloP100: 7.98

Genes affected

PAH (HGNC:8582): (phenylalanine hydroxylase) This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 9 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.1139C>T	p.Thr380Met	missense_variant	11/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.1139C>T	p.Thr380Met	missense_variant	12/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.1139C>T	p.Thr380Met	missense_variant	11/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000442 AC: 111 AN: 251264 Hom.: 1 AF XY: 0.000420 AC XY: 57 AN XY: 135790

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00476

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000387 AC: 566 AN: 1461372 Hom.: 1 Cov.: 33 AF XY: 0.000373 AC XY: 271 AN XY: 727026

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00478

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000327

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.000375 AC: 57 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74426

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000493 Hom.: 1

Bravo AF: 0.000366

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000329 AC: 40

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.00107

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:30 Uncertain:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:21

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The PAH c.1139C>T (p.Thr380Met) missense variant has been reported in at least 14 studies in which it is found in a total of 24 patients with phenylalanine hydroxylase deficiency including in 19 in a compound heterozygous state, and five in a heterozygous state (Guldberg et al. 1993; Zschocke et al. 1994; Zschocke et al. 1995; Kayaalp et al. 1997; Zekanowski et al. 1997; Pérez et al. 1997; Tyfield et al. 1997; Guldberg et al. 1998; Yang et al. 2001; Ho et al. 2014; Liu et al 2015). The p.Thr380Met variant was found in 1.2 - 5% of alleles tested in subsequent studies of PAH deficiency (Desviat et al. 1999; Bercovich et al. 2008; Okano et al. 2011). Control data are unavailable for this variant from these studies, which is reported at a frequency of 0.0007 in the European American population of the Exome Sequencing Project. In functional studies by Heintz et al. (2012), the p.Thr380Met variant enzyme was shown to have a reduced activity of 38% compared to the wild type. This residual activity is consistent with the milder phenotype associated with this variant. The variant created a new exonic splice enhancer resulting in a stronger definition of exon 11 of the PAH gene, having a positive effect on splicing and the inclusion of exon 11. RNA affinity binding and Western blotting analysis showed that the p.Thr380Met variant abolished the normal binding of three splicing factors seen in the wild type. When found with a severe PAH variant, the p.Thr380Met variant is thought be involved in mild elevations of serum phenylalanine. These patients do not require dietary treatment. Based on the collective evidence, the p.Thr380Met variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PAH c.1139C>T (p.Thr380Met) missense variant has been reported in at least 14 studies in which it is found in a total of 24 patients with phenylalanine hydroxylase deficiency including in 19 in a compound heterozygous state, and five in a heterozygous state (Guldberg et al. 1993; Zschocke et al. 1994; Zschocke et al. 1995; Kayaalp et al. 1997; Zekanowski et al. 1997; Pérez et al. 1997; Tyfield et al. 1997; Guldberg et al. 1998; Yang et al. 2001; Ho et al. 2014; Liu et al 2015). The p.Thr380Met variant was found in 1.2 - 5% of alleles tested in subsequent studies of PAH deficiency (Desviat et al. 1999; Bercovich et al. 2008; Okano et al. 2011). Control data are unavailable for this variant from these studies, which is reported at a frequency of 0.0007 in the European American population of the Exome Sequencing Project. In functional studies by Heintz et al. (2012), the p.Thr380Met variant enzyme was shown to have a reduced activity of 38% compared to the wild type. This residual activity is consistent with the milder phenotype associated with this variant. The variant created a new exonic splice enhancer resulting in a stronger definition of exon 11 of the PAH gene, having a positive effect on splicing and the inclusion of exon 11. RNA affinity binding and Western blotting analysis showed that the p.Thr380Met variant abolished the normal binding of three splicing factors seen in the wild type. When found with a severe PAH variant, the p.Thr380Met variant is thought be involved in mild elevations of serum phenylalanine. These patients do not require dietary treatment. The variant was identified in dbSNP (rs62642937) and ClinVar (classified as pathogenic by multiple sources) databases. The variant was identified in control databases in 181 of 282,648 alleles (1 homozygous) at a frequency of 0.04%, and was observed at the highest frequency in the Ashkenazi Jewish population in 10,364 of 282,648 alleles (freq: 0.47%) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.Thr380Met residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. Based on the collective evidence, the p.Thr380Met variant is classified as pathogenic for phenylalanine hydroxylase deficiency.  -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000277.1(PAH):c.1139C>T(T380M) is classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 27620137, 22698810, 8830172, 10598814, 17096675, 23792259, 9012412, 10394930, 26666653, 27243974, 8533759, 26542770, 23357515, 12655553, 16198137, 9298832, 27121329, 14722928, 18294361, 18299955, 23500595, 8268925, 21307867, 9634518, 23932990, 10693064, 16198137, 8533759, 11385716, 22698810, 24350308, 17924342, 21147011 and 24368688. Classification of NM_000277.1(PAH):c.1139C>T(T380M) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 09, 2024	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 phenylketonuria (MIM#261600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (116 heterozygotes, 1 homozygote). (SP) 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 Biopterin H domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is classified as pathogenic by an expert panel in ClinVar. This variant has been observed in multiple compound heterozygote individuals with hyperphenylalaninemia (PMID: 7981714,8268925), as well as a few homozygous or compound heterozygote individuals with phenylketonuria (PMID: 36937954, 24368688). (SP) 1207 - Parental origin of the variant is unresolved (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jul 26, 2016	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Oct 01, 2018	The c.1139C>T (p.Thr380Met) variant in PAH has been reported in 1 patient with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 8268925). This variant has 28% enzyme activity (PS3; PMID: 27620137). This variant was detected in trans with multiple known pathogenic variants: R408W, R261Q, I65T, F299C (PM3_Very-strong; PMID: 7981714). Computational prediction tools and conservation analysis suggest that the c.1139C>T variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3_Very-strong -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Jul 21, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.042%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 27620137). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.99). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 7981714). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 08, 2014	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	May 19, 2016	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Oct 17, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2022	The p.Thr380Met variant in PAH has been reported in at least seven individuals with phenylalanine hydroxylase deficiency including six compound heterozygotes of which five have pathogenic variants in trans as classified by the ClinGen PAH Variant Curation Expert Panel (Guldberg 1993 PMID: 8268925, Guo 2018 PMID: 29731766, Zschocke 1994 PMID: 7981714). It has also been identified in 0.52% (18/3472) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar as pathogenic by the ClinGen PAH Variant Curation Expert Panel using the . ACMG-AMP criteria specific for phenylalanine hydroxylase variants (Zastrow 2018 PMID: 30311390) and is curated in the FDA-recognized human genetic variant database (Variation ID 628). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function and decreases PAH activity to 28% (Trunzo 2016 PMID: 27620137); however, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive phenylalanine hydroxylase deficiency. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3, PP3, PP4_Moderate, BS1_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 380 of the PAH protein (p.Thr380Met). This variant is present in population databases (rs62642937, gnomAD 0.5%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with mild phenylketonuria (PKU) or mild hyperphenylalaninemia (HPA) (PMID: 8268925, 8533759, 9429153, 10598814, 14722928, 18299955, 23500595, 26600521, 26666653; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 628). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 22698810, 27620137). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:5 Uncertain:1 Other:1

Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2019	Functional analysis demonstrates that T380M is associated with 38% of wildtype PAH enzyme activity (Heintz et al., 2012); This variant is associated with the following publications: (PMID: 26990548, 23500595, 23792259, 31355225, 12655544, 17935162, 25087612, 25333069, 8268925, 27620137, 22698810, 30337205, 30747360, 29731766, 31980526, 30275481, 31589614, 32668217) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 14, 2021	This variant is associated with mild hyperphenylalaninemia when present with any other disease-causing variant in the PAH gene (PMIDs: 7981714 (1994), 8533759 (1995), 8268925 (1993), 18294361 (2008), 23500595 (2013), 26600521 (2015), 27121329 (2016), 33803550 (2021)), and is present in a significant percentage of individuals with PAH deficiency (PMIDs: 10234516 (1999), 21307867 (2011), and 27121329 (2016)). Additionally, multiple functional studies have indicated this variant has reduced activity compared to wild type and may affect splicing (PMIDs: 22698810 (2012) and 27620137 (2016)). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2021	- -

PAH-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 23, 2024

The PAH c.1139C>T variant is predicted to result in the amino acid substitution p.Thr380Met. This variant has been reported in multiple studies as causative for mild hyperphenylalaninemia (HPA) when in the compound heterozygous state with a second causative PAH variant (e.g., Mallolas et al. 1999. PubMed ID: 10598814; Bercovich et al. 2008. PubMed ID: 18299955; Heintz et al. 2012. PubMed ID: 22698810; Aldámiz-Echevarría et al. 2016. PubMed ID: 27121329). In in vitro expression assays, the p.Thr380Met substitution reduced the activity of the PAH enzyme to ~28-38% of control (Heintz et al. 2012. PubMed ID: 22698810; Trunzo et al. 2016. PubMed ID: 27620137). The p.Thr380Met amino acid substitution has been reported to result in a mutant PAH protein that is responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). The c.1139C>T variant has been reported at an allele frequency of 0.46%, including 1 homozygous individual, in an Ashkenazi Jewish population; in other populations, it is observed less frequently (i.e., <0.1%). This variant is classified as pathogenic in the ClinVar database by the ClinGen PAH Variant Curation Expert Panel and multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/628/). In summary, this variant is classified as pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2023

The c.1139C>T (p.T380M) alteration is located in exon 11 (coding exon 11) of the PAH gene. This alteration results from a C to T substitution at nucleotide position 1139, causing the threonine (T) at amino acid position 380 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of 0.042% (118/282648) total alleles studied. The highest observed frequency was 0.473% (49/10364) of Ashkenazi Jewish alleles. This alteration was detected in the homozygous state and in conjunction with another alteration in PAH in multiple individuals with phenylalanine hydroxylase deficiency (Martín-Rivada, 2022; Odagiri,2021; Aldámiz-Echevarría, 2016; Bayat, 2016; Bercovich, 2008; Bercovich, 2008; Fiori, 2005; Mallolas, 1999, Zekanowski, 1997). This amino acid position is highly conserved in available vertebrate species. Functional assays show reduced enzyme activity in vitro (Heintz, 2012; Trunzo, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Hyperphenylalaninemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1994

- -

6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 02, 2020

Variant summary: PAH c.1139C>T (p.Thr380Met) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 251264 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Hyperphenylalaninemia (0.00044 vs 0.0079), allowing no conclusion about variant significance. c.1139C>T has been reported in the literature in multiple individuals affected with Hyperphenylalaninemia (example, Ho_2013, Zschocke_1995, Bercovich_2008, Guldberg_1998, Heintz_2012, Zekanowski_1997). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Heintz_2012). The most pronounced variant effect results in 30%-50% of normal PAH activity. Multiple clinical diagnostic laboratories and one expert panel (ClinGen PAH Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Marfanoid habitus and intellectual disability Uncertain:1

Uncertain significance, flagged submission

research

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.3	H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;.
Vest4		0.90
MVP		0.99
MPC		0.24
ClinPred		0.30	T
GERP RS		5.3
Varity_R		0.79
gMVP		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs62642937; hg19: chr12-103237484;