rs6961

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. V644V) has been classified 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:15
• Conservation: PhyloP100: -0.891
• Publications: 23 publications found

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]

SDHA Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• pheochromocytoma/paraganglioma syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• mitochondrial complex II deficiency, nuclear type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• neurodegeneration with ataxia and late-onset optic atrophy

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics, ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• gastrointestinal stromal tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex II deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1GG

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000286001 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 130278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004168.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	NM_004168.4	MANE Select	c.1932G>A	p.Val644Val	synonymous	Exon 15 of 15	NP_004159.2
	SDHA	NM_001294332.2		c.1788G>A	p.Val596Val	synonymous	Exon 14 of 14	NP_001281261.1
	SDHA	NM_001330758.2		c.1689G>A	p.Val563Val	synonymous	Exon 13 of 13	NP_001317687.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	ENST00000264932.11	TSL:1 MANE Select	c.1932G>A	p.Val644Val	synonymous	Exon 15 of 15	ENSP00000264932.6
	ENSG00000286001	ENST00000651543.1		n.*665G>A		non_coding_transcript_exon	Exon 14 of 24	ENSP00000499215.1
	ENSG00000286001	ENST00000651543.1		n.*665G>A		3_prime_UTR	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

GnomAD2 exomes AF: 0.157 AC: 38347 AN: 244746 AF XY: 0.147

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 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

African (AFR) AF: 0.577 AC: 18369 AN: 31812

American (AMR) AF: 0.236 AC: 8928 AN: 37858

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 4542 AN: 23192

East Asian (EAS) AF: 0.0642 AC: 2253 AN: 35112

South Asian (SAS) AF: 0.112 AC: 8501 AN: 75992

European-Finnish (FIN) AF: 0.110 AC: 5080 AN: 46366

Middle Eastern (MID) AF: 0.221 AC: 976 AN: 4422

European-Non Finnish (NFE) AF: 0.219 AC: 184481 AN: 844200

Other (OTH) AF: 0.216 AC: 10786 AN: 49918

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

African (AFR) AF: 0.538 AC: 21947 AN: 40820

American (AMR) AF: 0.234 AC: 3380 AN: 14442

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 577 AN: 3360

East Asian (EAS) AF: 0.0594 AC: 287 AN: 4834

South Asian (SAS) AF: 0.0964 AC: 433 AN: 4490

European-Finnish (FIN) AF: 0.0905 AC: 888 AN: 9808

Middle Eastern (MID) AF: 0.222 AC: 64 AN: 288

European-Non Finnish (NFE) AF: 0.132 AC: 8522 AN: 64324

Other (OTH) AF: 0.246 AC: 490 AN: 1988

Alfa AF: 0.188 Hom.: 1667

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Pheochromocytoma/paraganglioma syndrome 5 (2)
-	-	1	Hereditary pheochromocytoma-paraganglioma (1)
-	-	1	Leigh syndrome (1)
-	-	1	Mitochondrial complex II deficiency, nuclear type 1 (1)
-	-	1	Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 (1)
-	-	1	SDHA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.93
DANN	Benign	0.60
PhyloP100		-0.89
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6961; hg19: chr5-256472; COSMIC: COSV53771746; COSMIC: COSV53771746;