rs6961

Variant names:

• chr5-256357-G-A
• rs6961
• NM_004168.4:c.1932G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004168.4(SDHA):​c.1932G>A​(p.Val644Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 1,294,100 control chromosomes in the GnomAD database, including 24,194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6936 hom., cov: 34)
  • Exomes 𝑓: 0.21 (17258 hom.)
• Consequence: SDHA NM_004168.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.891

Genes affected

SDHA (HGNC:10680): (succinate dehydrogenase complex flavoprotein subunit A) This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

ENSG00000286001 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 5-256357-G-A is Benign according to our data. Variant chr5-256357-G-A is described in ClinVar as [Benign]. Clinvar id is 130278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-256357-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.891 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4	c.1932G>A	p.Val644Val	synonymous_variant	Exon 15 of 15	ENST00000264932.11	NP_004159.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11	c.1932G>A	p.Val644Val	synonymous_variant	Exon 15 of 15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.*665G>A		non_coding_transcript_exon_variant	Exon 14 of 24			ENSP00000499215.1
ENSG00000286001	ENST00000651543.1	n.*665G>A		3_prime_UTR_variant	Exon 14 of 24			ENSP00000499215.1

Frequencies

GnomAD3 genomes AF: 0.254 AC: 36794 AN: 145118 Hom.: 6908 Cov.: 34

Gnomad AFR AF: 0.537

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.0598

Gnomad SAS AF: 0.0961

Gnomad FIN AF: 0.0905

Gnomad MID AF: 0.216

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.250

GnomAD3 exomes AF: 0.157 AC: 38347 AN: 244746 Hom.: 4495 AF XY: 0.147 AC XY: 19469 AN XY: 132436

Gnomad AFR exome AF: 0.555

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.0631

Gnomad SAS exome AF: 0.0919

Gnomad FIN exome AF: 0.0894

Gnomad NFE exome AF: 0.132

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.212 AC: 243916 AN: 1148872 Hom.: 17258 Cov.: 36 AF XY: 0.205 AC XY: 118302 AN XY: 576002

Gnomad4 AFR exome AF: 0.577

Gnomad4 AMR exome AF: 0.236

Gnomad4 ASJ exome AF: 0.196

Gnomad4 EAS exome AF: 0.0642

Gnomad4 SAS exome AF: 0.112

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.219

Gnomad4 OTH exome AF: 0.216

GnomAD4 genome AF: 0.254 AC: 36868 AN: 145228 Hom.: 6936 Cov.: 34 AF XY: 0.249 AC XY: 17598 AN XY: 70602

Gnomad4 AFR AF: 0.538

Gnomad4 AMR AF: 0.234

Gnomad4 ASJ AF: 0.172

Gnomad4 EAS AF: 0.0594

Gnomad4 SAS AF: 0.0964

Gnomad4 FIN AF: 0.0905

Gnomad4 NFE AF: 0.132

Gnomad4 OTH AF: 0.246

Alfa AF: 0.188 Hom.: 1667

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Jan 03, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mitochondrial complex II deficiency, nuclear type 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Leigh syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Nov 18, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

SDHA-related disorder Benign:1

Jun 02, 2022

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Paragangliomas 5 Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary pheochromocytoma-paraganglioma Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.93
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6961; hg19: chr5-256472; COSMIC: COSV53771746; COSMIC: COSV53771746;