Genetic Variant SDHAF4:p.Ser4Trp (chr6-70566951-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_145267.3(SDHAF4):c.11C>G(p.Ser4Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 1,587,854 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SDHAF4
NM_145267.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.01

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:

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ACMG classification

Classification made for transcript

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=0.15231872).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHAF4	NM_145267.3 link	c.11C>G	p.Ser4Trp	missense_variant	Exon 1 of 3	ENST00000370474.4	NP_660310.2	Q5VUM1
SDHAF4	XM_047418210.1 link	c.11C>G	p.Ser4Trp	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.11C>G	p.Ser4Trp	missense_variant	Exon 1 of 3	1	NM_145267.3	ENSP00000359505.3		Q5VUM1
SDHAF4	ENST00000468640.1 link	n.35C>G		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.00000487

AC:

AN:

205218

Hom.:

AF XY:

0.00

AC XY:

AN XY:

110392

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000112

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000118

AC:

AN:

1435610

Hom.:

Cov.:

AF XY:

0.00000562

AC XY:

AN XY:

711400

show subpopulations

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:

0.0000146

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

6.9

DANN

Benign

0.96

DEOGEN2

Benign

0.022

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.54

M_CAP

Benign

0.011

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.1

PROVEAN

Benign

-2.0

REVEL

Benign

0.050

Sift

Benign

0.052

Sift4G

Benign

0.064

Polyphen

0.95

Vest4

0.40

MutPred

0.24

Loss of disorder (P = 7e-04);

MVP

0.15

MPC

0.30

ClinPred

0.80

GERP RS

-0.36

Varity_R

0.049

gMVP

0.25

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over