rs149277592

Positions:

• chr11-61430153-G-A
• chr11-61430153-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017841.4(SDHAF2):​c.7G>A​(p.Val3Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SDHAF2 NM_017841.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.812

Genes affected

SDHAF2 (HGNC:26034): (succinate dehydrogenase complex assembly factor 2) This gene encodes a mitochondrial assembly factor needed for the flavination of a succinate dehydrogenase complex subunit (SDHA), which is required for activity of the succinate dehydrogenase complex. Mutations in this gene are associated with paraganglioma. [provided by RefSeq, May 2022]

ENSG00000256591 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06952405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHAF2	NM_017841.4	c.7G>A	p.Val3Met	missense_variant	1/4	ENST00000301761.7	NP_060311.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHAF2	ENST00000301761.7	c.7G>A	p.Val3Met	missense_variant	1/4	1	NM_017841.4	ENSP00000301761.3
ENSG00000256591	ENST00000541135.5	c.7G>A	p.Val3Met	missense_variant	1/5	4		ENSP00000443130.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461842 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2019

The p.V3M variant (also known as c.7G>A), located in coding exon 1 of the SDHAF2 gene, results from a G to A substitution at nucleotide position 7. The valine at codon 3 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by BayesDel in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	.;T;.;.;.;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.61	T;T;T;T;T;T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.070	T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.0	.;M;.;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.22	N;N;.;.;.;N
REVEL	Benign	0.074
Sift	Benign	0.089	T;T;.;.;.;T
Sift4G	Benign	0.091	T;D;.;D;D;D
Polyphen		0.23	.;B;.;.;.;.
Vest4		0.23, 0.23, 0.19, 0.27, 0.23
MutPred		0.19		Loss of catalytic residue at V3 (P = 0.0102);Loss of catalytic residue at V3 (P = 0.0102);Loss of catalytic residue at V3 (P = 0.0102);Loss of catalytic residue at V3 (P = 0.0102);Loss of catalytic residue at V3 (P = 0.0102);Loss of catalytic residue at V3 (P = 0.0102);
MVP		0.25
MPC		0.29
ClinPred		0.60	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.038
gMVP		0.30

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: rs149277592; hg19: chr11-61197625; COSMIC: COSV57099956; COSMIC: COSV57099956;