Genetic Variant NM_017841.4:c.10T>G (chr11-61430156-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017841.4(SDHAF2):c.10T>G(p.Ser4Ala) 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. 17/22 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. S4C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

SDHAF2
NM_017841.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.00600

Publications

0 publications found

Variant links:

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]

SDHAF2 links:

ENSG00000256591 (HGNC:):

ENSG00000256591 links:

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]

CPSF7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.023432076).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017841.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SDHAF2	NM_017841.4	MANE Select	c.10T>G	p.Ser4Ala	missense	Exon 1 of 4	NP_060311.1	Q9NX18
CPSF7	NM_001142565.3	MANE Select	c.-298A>C		upstream_gene	N/A	NP_001136037.1	Q8N684-2
CPSF7	NM_024811.4		c.-326A>C		upstream_gene	N/A	NP_079087.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SDHAF2	ENST00000301761.7	TSL:1 MANE Select	c.10T>G	p.Ser4Ala	missense	Exon 1 of 4	ENSP00000301761.3	Q9NX18
ENSG00000256591	ENST00000541135.5	TSL:4	c.10T>G	p.Ser4Ala	missense	Exon 1 of 5	ENSP00000443130.1	F5H5T6
SDHAF2	ENST00000713963.1		c.10T>G	p.Ser4Ala	missense	Exon 1 of 5	ENSP00000519256.1	A0AAQ5BH90

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary pheochromocytoma-paraganglioma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

3.7

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.013

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0012

LIST_S2

Benign

0.12

M_CAP

Benign

0.049

MetaRNN

Benign

0.023

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-1.6

PhyloP100

0.0060

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.22

REVEL

Benign

0.12

Sift

Benign

0.98

Sift4G

Benign

0.77

Polyphen

0.0

Vest4

0.15

MVP

0.16

MPC

0.14

ClinPred

0.070

GERP RS

0.68

PromoterAI

0.053

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.046

gMVP

0.27

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over