11-61430150-G-T

Variant names:

• chr11-61430150-G-T
• NM_017841.4:c.4G>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.4G>T​(p.Ala2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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)
• Consequence: SDHAF2 NM_017841.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82

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=0.19241616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHAF2	NM_017841.4	c.4G>T	p.Ala2Ser	missense_variant	Exon 1 of 4	ENST00000301761.7	NP_060311.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHAF2	ENST00000301761.7	c.4G>T	p.Ala2Ser	missense_variant	Exon 1 of 4	1	NM_017841.4	ENSP00000301761.3
ENSG00000256591	ENST00000541135.5	c.4G>T	p.Ala2Ser	missense_variant	Exon 1 of 5	4		ENSP00000443130.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Dec 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A2S variant (also known as c.4G>T), located in coding exon 1 of the SDHAF2 gene, results from a G to T substitution at nucleotide position 4. The alanine at codon 2 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by 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	0.11
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.026	.;T;.;.;.;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.44	T;T;T;T;T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.19	T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.8	.;L;.;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.030	N;N;.;.;.;N
REVEL	Benign	0.13
Sift	Benign	0.044	D;T;.;.;.;T
Sift4G	Benign	0.19	T;T;.;T;T;T
Polyphen		0.0070	.;B;.;.;.;.
Vest4		0.25, 0.27, 0.22, 0.26, 0.28
MutPred		0.16		Gain of phosphorylation at A2 (P = 0.0408);Gain of phosphorylation at A2 (P = 0.0408);Gain of phosphorylation at A2 (P = 0.0408);Gain of phosphorylation at A2 (P = 0.0408);Gain of phosphorylation at A2 (P = 0.0408);Gain of phosphorylation at A2 (P = 0.0408);
MVP		0.39
MPC		0.16
ClinPred		0.28	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.047
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-61197622;