rs34635677

Variant names:

• chr5-223531-A-T
• rs34635677
• NM_004168.4:c.113A>T

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.113A>T​(p.Asp38Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0425 in 1,613,484 control chromosomes in the GnomAD database, including 1,760 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D38G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.029 (84 hom., cov: 33)
  • Exomes 𝑓: 0.044 (1676 hom.)
• Consequence: SDHA NM_004168.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 2.74
• Publications: 26 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, Labcorp Genetics (formerly Invitae), Illumina, G2P
• mitochondrial complex II deficiency, nuclear type 1

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

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=0.002396673).
• BP6: Variant 5-223531-A-T is Benign according to our data. Variant chr5-223531-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 224957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0518 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.113A>T	p.Asp38Val	missense	Exon 2 of 15	NP_004159.2
	SDHA	NM_001294332.2		c.113A>T	p.Asp38Val	missense	Exon 2 of 14	NP_001281261.1
	SDHA	NM_001330758.2		c.113A>T	p.Asp38Val	missense	Exon 2 of 13	NP_001317687.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	ENST00000264932.11	TSL:1 MANE Select	c.113A>T	p.Asp38Val	missense	Exon 2 of 15	ENSP00000264932.6
	ENSG00000286001	ENST00000651543.1		n.113A>T		non_coding_transcript_exon	Exon 2 of 24	ENSP00000499215.1
	SDHA	ENST00000874235.1		c.113A>T	p.Asp38Val	missense	Exon 2 of 16	ENSP00000544294.1

Frequencies

GnomAD3 genomes AF: 0.0295 AC: 4494 AN: 152212 Hom.: 83 Cov.: 33

Gnomad AFR AF: 0.00827

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.0507

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0569

Gnomad FIN AF: 0.0255

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0448

Gnomad OTH AF: 0.0339

GnomAD2 exomes AF: 0.0351 AC: 8822 AN: 251180 AF XY: 0.0381

Gnomad AFR exome AF: 0.00634

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.0503

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0251

Gnomad NFE exome AF: 0.0456

Gnomad OTH exome AF: 0.0375

GnomAD4 exome AF: 0.0438 AC: 64049 AN: 1461154 Hom.: 1676 Cov.: 30 AF XY: 0.0446 AC XY: 32425 AN XY: 726914

African (AFR) AF: 0.00547 AC: 183 AN: 33470

American (AMR) AF: 0.0144 AC: 645 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0503 AC: 1314 AN: 26130

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0604 AC: 5205 AN: 86234

European-Finnish (FIN) AF: 0.0243 AC: 1298 AN: 53418

Middle Eastern (MID) AF: 0.0437 AC: 252 AN: 5762

European-Non Finnish (NFE) AF: 0.0475 AC: 52761 AN: 1111366

Other (OTH) AF: 0.0395 AC: 2385 AN: 60358

GnomAD4 genome AF: 0.0295 AC: 4491 AN: 152330 Hom.: 84 Cov.: 33 AF XY: 0.0283 AC XY: 2109 AN XY: 74502

African (AFR) AF: 0.00825 AC: 343 AN: 41576

American (AMR) AF: 0.0195 AC: 299 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0507 AC: 176 AN: 3470

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5194

South Asian (SAS) AF: 0.0574 AC: 277 AN: 4828

European-Finnish (FIN) AF: 0.0255 AC: 271 AN: 10614

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0448 AC: 3046 AN: 68032

Other (OTH) AF: 0.0331 AC: 70 AN: 2114

Alfa AF: 0.0434 Hom.: 101

Bravo AF: 0.0270

TwinsUK AF: 0.0507 AC: 188

ALSPAC AF: 0.0472 AC: 182

ESP6500AA AF: 0.00794 AC: 35

ESP6500EA AF: 0.0456 AC: 392

ExAC AF: 0.0353 AC: 4285

Asia WGS AF: 0.0210 AC: 73 AN: 3478

EpiCase AF: 0.0459

EpiControl AF: 0.0458

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Pheochromocytoma/paraganglioma syndrome 5 (2)
-	-	1	Dilated cardiomyopathy 1GG (1)
-	-	1	Dilated cardiomyopathy 1GG;C3279992:Pheochromocytoma/paraganglioma syndrome 5;C5543254:Neurodegeneration with ataxia and late-onset optic atrophy;C5700310:Mitochondrial complex II deficiency, nuclear type 1 (1)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N
PhyloP100		2.7
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.078
Sift	Benign	0.61	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.37
MPC		0.69
ClinPred		0.0011	T
GERP RS		1.6
Varity_R		0.050
gMVP		0.57
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs34635677; hg19: chr5-223646; COSMIC: COSV53772162;