rs6962

Variant names:

• chr5-256394-G-A
• rs6962
• NM_004168.4:c.1969G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-256394-G-A
• chr5-256394-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004168.4(SDHA):​c.1969G>A​(p.Val657Ile) variant causes a missense change. The variant allele was found at a frequency of 0.128 in 1,605,264 control chromosomes in the GnomAD database, including 11,138 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2763 hom., cov: 34)
  • Exomes 𝑓: 0.12 (8375 hom.)
• Consequence: SDHA NM_004168.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 4.70

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011221588).
• BP6: Variant 5-256394-G-A is Benign according to our data. Variant chr5-256394-G-A is described in ClinVar as [Benign]. Clinvar id is 130279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-256394-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4	c.1969G>A	p.Val657Ile	missense_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.1969G>A	p.Val657Ile	missense_variant	Exon 15 of 15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.*702G>A		non_coding_transcript_exon_variant	Exon 14 of 24			ENSP00000499215.1
ENSG00000286001	ENST00000651543.1	n.*702G>A		3_prime_UTR_variant	Exon 14 of 24			ENSP00000499215.1

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26620 AN: 151644 Hom.: 2756 Cov.: 34

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.0559

Gnomad SAS AF: 0.0850

Gnomad FIN AF: 0.0812

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.177

GnomAD3 exomes AF: 0.131 AC: 32957 AN: 250898 Hom.: 2221 AF XY: 0.126 AC XY: 17130 AN XY: 135600

Gnomad AFR exome AF: 0.324

Gnomad AMR exome AF: 0.169

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.0602

Gnomad SAS exome AF: 0.0879

Gnomad FIN exome AF: 0.0855

Gnomad NFE exome AF: 0.123

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.123 AC: 178656 AN: 1453502 Hom.: 8375 Cov.: 35 AF XY: 0.121 AC XY: 87874 AN XY: 723584

Gnomad4 AFR exome AF: 0.308

Gnomad4 AMR exome AF: 0.163

Gnomad4 ASJ exome AF: 0.153

Gnomad4 EAS exome AF: 0.0476

Gnomad4 SAS exome AF: 0.0871

Gnomad4 FIN exome AF: 0.0873

Gnomad4 NFE exome AF: 0.122

Gnomad4 OTH exome AF: 0.131

GnomAD4 genome AF: 0.176 AC: 26650 AN: 151762 Hom.: 2763 Cov.: 34 AF XY: 0.170 AC XY: 12640 AN XY: 74186

Gnomad4 AFR AF: 0.316

Gnomad4 AMR AF: 0.178

Gnomad4 ASJ AF: 0.156

Gnomad4 EAS AF: 0.0554

Gnomad4 SAS AF: 0.0855

Gnomad4 FIN AF: 0.0812

Gnomad4 NFE AF: 0.120

Gnomad4 OTH AF: 0.174

Alfa AF: 0.112 Hom.: 433

Bravo AF: 0.196

TwinsUK AF: 0.128 AC: 474

ALSPAC AF: 0.129 AC: 496

ESP6500AA AF: 0.326 AC: 1438

ESP6500EA AF: 0.130 AC: 1117

ExAC AF: 0.131 AC: 15857

Asia WGS AF: 0.0970 AC: 341 AN: 3478

EpiCase AF: 0.132

EpiControl AF: 0.128

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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:2

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not specified Benign:1

-

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. -

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. -

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

- -

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). -

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
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.72
DEOGEN2	Benign	0.24	T;T;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T;T;T;T
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;L;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.45	.;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.33	.;T;T;T
Sift4G	Benign	0.58	T;T;T;T
Polyphen		0.021, 0.013	.;B;B;.
Vest4		0.15
MPC		0.41
ClinPred		0.017	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.031
gMVP		0.50

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: rs6962; hg19: chr5-256509; COSMIC: COSV53765963; COSMIC: COSV53765963;