Genetic Variant NM_145267.3:c.52T>C (chr6-70566992-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_145267.3(SDHAF4):c.52T>C(p.Trp18Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000667 in 1,589,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

SDHAF4
NM_145267.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.361

Variant links:

Genes affected

SDHAF4 (HGNC:20957): (succinate dehydrogenase complex assembly factor 4) Predicted to enable enzyme activator activity. Involved in cellular respiration and mitochondrial respiratory chain complex II assembly. Predicted to be located in mitochondrial matrix. Predicted to be active in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

SDHAF4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.021160275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHAF4	NM_145267.3 link	c.52T>C	p.Trp18Arg	missense_variant	Exon 1 of 3	ENST00000370474.4	NP_660310.2	Q5VUM1
SDHAF4	XM_047418210.1 link	c.52T>C	p.Trp18Arg	missense_variant	Exon 1 of 3		XP_047274166.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHAF4	ENST00000370474.4 link	c.52T>C	p.Trp18Arg	missense_variant	Exon 1 of 3	1	NM_145267.3	ENSP00000359505.3		Q5VUM1
SDHAF4	ENST00000468640.1 link	n.76T>C		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000142

AC:

AN:

204308

Hom.:

AF XY:

0.000182

AC XY:

AN XY:

109940

show subpopulations

Gnomad AFR exome

AF:

0.0000822

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00251

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000452

Gnomad OTH exome

AF:

0.000191

GnomAD4 exome

AF:

0.0000619

AC:

AN:

1437368

Hom.:

Cov.:

AF XY:

0.0000547

AC XY:

AN XY:

712502

show subpopulations

Gnomad4 AFR exome

AF:

0.0000303

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00254

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000909

Gnomad4 OTH exome

AF:

0.000219

GnomAD4 genome

AF:

0.000112

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000329

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.0000831

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.52T>C (p.W18R) alteration is located in exon 1 (coding exon 1) of the SDHAF4 gene. This alteration results from a T to C substitution at nucleotide position 52, causing the tryptophan (W) at amino acid position 18 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.64

DEOGEN2

Benign

0.019

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.28

M_CAP

Benign

0.0032

MetaRNN

Benign

0.021

MetaSVM

Benign

-0.95

PROVEAN

Benign

-1.9

REVEL

Benign

0.048

Sift

Benign

0.069

Sift4G

Uncertain

0.030

Polyphen

0.0010

Vest4

0.53

MutPred

0.52

Gain of disorder (P = 8e-04);

MVP

0.12

MPC

0.16

ClinPred

0.025

GERP RS

-0.14

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.28

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over