chr1-17022648-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_003000.3(SDHB):c.725G>A(p.Arg242His) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,846 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R242C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SDHB
NM_003000.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: 5.63

Variant links:

Genes affected

SDHB (HGNC:10681): (succinate dehydrogenase complex iron sulfur subunit B) This tumor suppressor gene encodes the iron-sulfur protein subunit of the succinate dehydrogenase (SDH) enzyme complex which plays a critical role in mitochondria. The SDH enzyme complex is composed of four nuclear-encoded subunits. This enzyme complex converts succinate to fumarate which releases electrons as part of the citric acid cycle, and the enzyme complex additionally provides an attachment site for released electrons to be transferred to the oxidative phosphorylation pathway. The SDH enzyme complex plays a role in oxygen-related gene regulation through its conversion of succinate, which is an oxygen sensor that stabilizes the hypoxia-inducible factor 1 (HIF1) transcription factor. Sporadic and familial mutations in this gene result in paragangliomas, pheochromocytoma, and gastrointestinal stromal tumors, supporting a link between mitochondrial dysfunction and tumorigenesis. Mutations in this gene are also implicated in nuclear type 4 mitochondrial complex II deficiency. [provided by RefSeq, Jun 2022]

SDHB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_003000.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-17022649-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 186827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 1-17022648-C-T is Pathogenic according to our data. Variant chr1-17022648-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17022648-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHB	NM_003000.3 link	c.725G>A	p.Arg242His	missense_variant	Exon 7 of 8	ENST00000375499.8	NP_002991.2	P21912
SDHB	NM_001407361.1 link	c.671G>A	p.Arg224His	missense_variant	Exon 7 of 8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8 link	c.725G>A	p.Arg242His	missense_variant	Exon 7 of 8	1	NM_003000.3	ENSP00000364649.3		P21912

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251440

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461722

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: significantly reduced SDH/complex II activity and abrogated SDHAF3 interaction (Kim et al., 2015; Nesti et al., 2015; Dwight et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); 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: 12213855, 19393419, 23433498, 25025441, 17102084, 29925701, 34906457, 32782288, 24606901, 22835832, 25736212, 12000816, 25972245, 21173220, 20208144, 22293219, 19258401, 17652212, 19802898, 22270996, 25047027, 19454582, 18551016, 28374168, 25899001, 27573198, 15328326, 24276837, 25873086, 19075037, 16317055, 28503760, 29386252, 29204718, 29951630, 29800631, 29950348, 28748451, 31212687, 30549360, 31104306, 30658386, 28490599, 31492822, 30050099, 26464466, 31589614, 32741965, 33644666, 30787465, 28738844) -

May 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 12, 2013

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population, 0.000012 (3/251440 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in multiple individuals affected with PGL-PCC syndrome (PMID: 12000816 (2002), 12213855 (2002), 18551016 (2008), 19351833 (2009), 29386252 (2018), 34439168 (2021), 34906457 (2022)). Functional studies observed decreased stability of the SDHB protein (PMID: 22835832 (2012)) and a severe decrease in succinate dehydrogenase activity (PMID: 25736212 (2015), 25972245 (2015)). Based on the available information, this variant is classified as pathogenic. -

Aug 02, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SDHB c.725G>A; p.Arg242His variant (rs74315368) is reported in the literature in individuals affected with paraganglioma or pheochromocytoma (Luiz 2013, Neumann 2002, Neumann 2009, Niemeijer 2017, Young 2002). In at least one family, this variant was observed to segregate with disease (Young 2002). This variant is also reported in ClinVar (Variation ID: 12781). It is only found on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.944). Consistent with these predictions, functional assays have observed that this variant exhibits decreased SDH/complex II activity (Kim 2015, Nesti 2015) and increased ubiquitination (Yang 2012). Additionally, other amino acid substitutions at this codon (p.Arg242Cys, p.Arg242Ser) have been reported in individuals with paraganglioma and are considered pathogenic (Badenhop 2004, Neumann 2009). Based on available information, the p.Arg242His variant is considered to be pathogenic. References: Badenhop RF et al. The prevalence of SDHB, SDHC, and SDHD mutations in patients with head and neck paraganglioma and association of mutations with clinical features. J Med Genet. 2004 Jul;41(7):e99. PMID: 15235042. Kim E et al. Structural and functional consequences of succinate dehydrogenase subunit B mutations. Endocr Relat Cancer. 2015 Jun;22(3):387-97. PMID: 25972245. Luiz HV et al. Malignant paraganglioma presenting with hemorrhagic stroke in a child. Pediatrics. 2013 Dec;132(6):e1709-14. PMID: 24276837. Nesti C et al. Additive effect of nuclear and mitochondrial mutations in a patient with mitochondrial encephalomyopathy. Hum Mol Genet. 2015 Jun 1;24(11):3248-56. PMID: 25736212. Neumann HP et al. Clinical predictors for germline mutations in head and neck paraganglioma patients: cost reduction strategy in genetic diagnostic process as fall-out. Cancer Res. 2009 Apr 15;69(8):3650-6. PMID: 19351833. Neumann HP et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002 May 9;346(19):1459-66. PMID: 12000816. Niemeijer ND et al. The phenotype of SDHB germline mutation carriers: a nationwide study. Eur J Endocrinol. 2017 Aug;177(2):115-125. PMID: 28490599. Yang C et al. Missense mutations in the human SDHB gene increase protein degradation without altering intrinsic enzymatic function. FASEB J. 2012 Nov;26(11):4506-16. PMID: 22835832. Young AL et al. Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene. J Clin Endocrinol Metab. 2002 Sep;87(9):4101-5. PMID: 12213855. -

Paragangliomas 4

Pathogenic:4

Jan 04, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 05, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 17, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP3. -

Feb 08, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30050099, 32462735, 33362715, 34439168]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Hereditary pheochromocytoma-paraganglioma

Pathogenic:4

Aug 08, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.725G>A variant in the SDHB gene is located on the exon 7 and is predicted to replace arginine with histidine at codon 242 (p.Arg242His). The variant has been reported in multiple unrelated individuals with paraganglioma/pheochromocytoma/renal cell carcinoma (PMID: 12000816, 32661476, 33748650, 36597280, 29925701, 33362715, 34906457). Alternative variants disrupting the same amino acid (p.Arg242Ser, p.Arg242Cys) have been interpreted as pathogenic (ClinVar ID: 239443, 186827). In vitro SDH activity assay and co-immunoprecipitation experiment in mammalian cells demonstrated impaired function and abolished interaction with the SDH aseembly factor SDHAF3 (PMID: 25972245, 28738844). The variant is reported in ClinVar (ID: 12781). The variant is rare in general population according to gnomAD (18/1613846 chromosomes, 0.001%) . Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.94). Therefore, the c.725G>A (p.Arg242His) variant in the SDHB gene is classified as pathogenic. -

Section on Medical Neuroendocrinolgy, National Institutes of Health

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Apr 27, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SDHB c.725G>A (p.Arg242His) results in a non-conservative amino acid change in 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 1.2e-05 in 251440 control chromosomes. c.725G>A has been reported in the literature in multiple individuals affected with features of Hereditary Paraganglioma-Pheochromocytoma Syndrome (example, Persu_2008, Amar_2007, Young_2002, Benn_2006, Neumann_2004, Neumann_2002). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12000816, 17652212, 16317055, 15328326, 18551016, 12213855). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 10, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SDHB c.725G>A variant is a single nucleotide substitution from a guanine to an adenonine at position 725 which is predicted to change the arginine at position 242 in the protein to histidine. The variant has been reported multiple times in the literature in association with disease (PMID: 12000816, 12213855, 15328326, 28490599) (PS1). Functional studies demonstrate that the variant has a detrimental effect on protein function (PMID: 25972245, 22835832) (PS3). The variant is listed in dbSNP (rs74315368) and is rare in population databases (gnomAD 3 het/251,440 total, 0 hom). The variant is described in ClinVar as pathogenic (ClinVar ID: 27820) and HGMD (2020.3) as disease causing (PP5). Computational predictions support a deleterious effect on the gene or gene product. -

Gastrointestinal stromal tumor

Pathogenic:2

Aug 20, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 04, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Nov 08, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R242H pathogenic mutation (also known as c.725G>A), located in coding exon 7 of the SDHB gene, results from a G to A substitution at nucleotide position 725. The arginine at codon 242 is replaced by histidine, an amino acid with highly similar properties. The p.R242H mutation has been well described in published literature. It has been identified in numerous individuals with tumors across the paraganglioma-pheochromocytoma (PGL-PCC) syndrome spectrum, including thoracic, pelvic, and head and neck PGL, adrenal PCC, and renal cell carcinoma (Neumann HP et al. JAMA. 2004 Aug;292:943-51; Ghayee HK et al. Endocr. Relat. Cancer. 2009 Mar;16:291-9; Luiz HV et al. Pediatrics. 2013 Dec;32:e1709-14; Persu A et al. J. Hypertens. 2008 Jul;26:1395-401; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94:2817-27; Merlo A et al. J. Clin. Endocrinol. Metab 2013 Oct;98:E1661-6; Rattenberry E et al. J. Clin. Endocrinol. Metab. 2013 Jul;98:E1248-56; van Hulsteijn LT et al. Fam. Cancer. 2014 Dec;13:651-7; Janssen I et al. Clin. Cancer Res. 2015 Sep;21:3888-95; Gill AJ et al. Am. J. Surg. Pathol. 2014 Dec;38:1588-602). In one study, mutant yeast strains with this mutation showed a significant defect and structural analysis suggested that this mutation alters the conformation of the protein, causing a decrease in the positive surface extent of the mutant protein (Nesti C et al. Hum. Mol. Genet. 2015 Jun;24:3248-56). Additionally, structural modeling of this mutation has predicted disruption of the electron path and impaired functional activity (Kim E et al. Endocr. Relat. Cancer. 2015 Jun;22:387-97). Of note, two different alterations at the same codon, p.R242C and p.R242S, have also been reported in patients with head/neck PGLs and PCCs (Panizza E et al. Hum. Mol. Genet. 2013 Feb;22:804-15; Neumann HP et al. Cancer Res. 2009 Apr;69:3650-6; Lefebvre S et al. Horm. Metab. Res. 2012 May;44:334-8; Badenhop RF et al. J. Med. Genet. 2004 Jul;41:e99). Based on the available evidence, this alteration is interpreted as a disease-causing mutation. -

Jul 06, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

SDHB-related disorder

Pathogenic:2

Feb 14, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 25972245; 25736212; 22835832) - PS3. The c.725G>A;p.(Arg242His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 12781; OMIM: 185470.0004; PMID: 12000816; 20208144; 24276837; 12213855; 17102084; 22270996) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Fer4) - PM1. This variant is not present in population databases (rs7431536, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 239443 - c.724C>A (p.Arg242Ser); ClinVar ID: 186827 - c.724C>T (p.Arg242Cys)) - PM5. Missense variant in SDHB that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. In summary, the currently available evidence indicates that the variant is pathogenic. -

Aug 14, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.725G>A (p.Arg242His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported as a heterozygous change in patients with hereditary paraganglioma-pheochromocytoma syndromes (PMID: 12000816, 12213855, 20208144, 21173220, 24276837, 25736212). The c.725G>A (p.Arg242His) variant is located in a mutational hotspot for pathogenic variations associated with hereditary paraganglioma-pheochromocytoma syndromes (PMID: 23175444, 15235042). Functional studies demonstrated that the c.725G>A (p.Arg242His) variant results in decreased stability of the SDHB protein and a severe decrease in succinate dehydrogenase activity (PMID: 25972245, 22835832, 25736212).The c.725G>A (p.Arg242His) variant is present in the latest version of the gnomAD population database at an allele frequency of 0.001% (18/1613846) and thus is presumed to be rare. Based on the available evidence, c.725G>A (p.Arg242His) is classified as Pathogenic. -

Mitochondrial complex 2 deficiency, nuclear type 4

Pathogenic:1

Feb 02, 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 mitochondrial complex II deficiency, nuclear type 4 (MIM#619224), pheochromocytoma (MIM#171300) and paragangliomas 4 (MIM#115310). (I) 0108 - This gene is associated with both recessive and dominant disease. However, the genotype-phenotype correlation is currently unestablished (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews). I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (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 4Fe-4S dicluster domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in several individuals with pheochromocytoma (MIM#171300) and/or paragangliomas 4 (MIM#115310), rarely in non-paraganglioma tumours such as gastrointestinal stromal tumour and a single case of mitochondrial encephalomyopathy (PMID: 32460727, 33748650, 28490599, 21173220, 25736212). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4

Pathogenic:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 242 of the SDHB protein (p.Arg242His). This variant is present in population databases (rs74315368, gnomAD 0.007%). This missense change has been observed in individuals with sporadic and familial hereditary paragangliomas and/or pheochromocytomas (PMID: 12000816, 12213855, 17102084, 20208144, 21173220, 22270996, 24276837, 25736212). ClinVar contains an entry for this variant (Variation ID: 12781). 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 SDHB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SDHB function (PMID: 22835832, 25736212, 25972245). This variant disrupts the p.Arg242 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MutPred

0.94

Loss of MoRF binding (P = 0.0969);

MVP

0.99

MPC

0.78

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.78

gMVP

0.89

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over