5-256394-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V657A) has been classified as Uncertain significance.

• 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:14
• Conservation: PhyloP100: 4.70
• Publications: 51 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: Ambry Genetics, Illumina, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• mitochondrial complex II deficiency, nuclear type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: ClinGen, Ambry Genetics
• 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 -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 VariationId is 130279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.311 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	NM_004168.4	MANE Select	c.1969G>A	p.Val657Ile	missense	Exon 15 of 15	NP_004159.2	P31040-1
	SDHA	NM_001294332.2		c.1825G>A	p.Val609Ile	missense	Exon 14 of 14	NP_001281261.1	P31040-2
	SDHA	NM_001330758.2		c.1726G>A	p.Val576Ile	missense	Exon 13 of 13	NP_001317687.1	D6RFM5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	ENST00000264932.11	TSL:1 MANE Select	c.1969G>A	p.Val657Ile	missense	Exon 15 of 15	ENSP00000264932.6	P31040-1
	ENSG00000286001	ENST00000651543.1		n.*702G>A		non_coding_transcript_exon	Exon 14 of 24	ENSP00000499215.1	A0A494C1T6
	ENSG00000286001	ENST00000651543.1		n.*702G>A		3_prime_UTR	Exon 14 of 24	ENSP00000499215.1	A0A494C1T6

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

GnomAD2 exomes AF: 0.131 AC: 32957 AN: 250898 AF XY: 0.126

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 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

African (AFR) AF: 0.308 AC: 10168 AN: 32986

American (AMR) AF: 0.163 AC: 7286 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 3980 AN: 26064

East Asian (EAS) AF: 0.0476 AC: 1890 AN: 39680

South Asian (SAS) AF: 0.0871 AC: 7500 AN: 86144

European-Finnish (FIN) AF: 0.0873 AC: 4662 AN: 53390

Middle Eastern (MID) AF: 0.101 AC: 582 AN: 5750

European-Non Finnish (NFE) AF: 0.122 AC: 134748 AN: 1104814

Other (OTH) AF: 0.131 AC: 7840 AN: 60060

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

African (AFR) AF: 0.316 AC: 13026 AN: 41226

American (AMR) AF: 0.178 AC: 2724 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 539 AN: 3466

East Asian (EAS) AF: 0.0554 AC: 287 AN: 5178

South Asian (SAS) AF: 0.0855 AC: 412 AN: 4818

European-Finnish (FIN) AF: 0.0812 AC: 859 AN: 10582

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8123 AN: 67920

Other (OTH) AF: 0.174 AC: 367 AN: 2110

Alfa AF: 0.121 Hom.: 740

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Mitochondrial complex II deficiency, nuclear type 1 (2)
-	-	2	Pheochromocytoma/paraganglioma syndrome 5 (2)
-	-	1	Hereditary pheochromocytoma-paraganglioma (1)
-	-	1	Leigh syndrome (1)
-	-	1	not specified (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
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
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.19
Sift	Benign	0.33	T
Sift4G	Benign	0.58	T
Polyphen		0.021	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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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