chr11-61430153-G-A

Variant names:

• chr11-61430153-G-A
• rs149277592
• NM_017841.4:c.7G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3L) has been classified as Likely benign.

• 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
• Publications: 3 publications found

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:):

CPSF7 (HGNC:30098): (cleavage and polyadenylation specific factor 7) Cleavage factor Im (CFIm) is one of six factors necessary for correct cleavage and polyadenylation of pre-mRNAs. CFIm is composed of three different subunits of 25, 59, and 68 kDa, and it functions as a heterotetramer, with a dimer of the 25 kDa subunit binding to two of the 59 or 68 kDa subunits. The protein encoded by this gene represents the 59 kDa subunit, which can interact with the splicing factor U2 snRNP Auxiliary Factor (U2AF) 65 to link the splicing and polyadenylation complexes. [provided by RefSeq, Oct 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
SDHAF2	NM_017841.4	c.7G>A	p.Val3Met	missense_variant	Exon 1 of 4	ENST00000301761.7	NP_060311.1
CPSF7	NM_001142565.3	c.-295C>T		upstream_gene_variant		ENST00000439958.8	NP_001136037.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHAF2	ENST00000301761.7	c.7G>A	p.Val3Met	missense_variant	Exon 1 of 4	1	NM_017841.4	ENSP00000301761.3
ENSG00000256591	ENST00000541135.5	c.7G>A	p.Val3Met	missense_variant	Exon 1 of 5	4		ENSP00000443130.1
CPSF7	ENST00000439958.8	c.-295C>T		upstream_gene_variant		1	NM_001142565.3	ENSP00000397203.3

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60392

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

Jun 13, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.;.;.;.
PhyloP100		0.81
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
PromoterAI		-0.041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.038
gMVP		0.30
Mutation Taster		=96/4	polymorphism

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