rs1048886

Positions:

• chr6-70579486-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_145267.3(SDHAF4):​c.137A>G​(p.Gln46Arg) variant causes a missense change. The variant allele was found at a frequency of 0.177 in 1,609,918 control chromosomes in the GnomAD database, including 26,366 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.21 (3800 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22566 hom.)
• Consequence: SDHAF4 NM_145267.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.83

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041306913).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHAF4	NM_145267.3	c.137A>G	p.Gln46Arg	missense_variant	2/3	ENST00000370474.4	NP_660310.2
SDHAF4	XM_047418210.1	c.137A>G	p.Gln46Arg	missense_variant	2/3		XP_047274166.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHAF4	ENST00000370474.4	c.137A>G	p.Gln46Arg	missense_variant	2/3	1	NM_145267.3	ENSP00000359505	P1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32207 AN: 152036 Hom.: 3778 Cov.: 32

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.236

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.208

GnomAD3 exomes AF: 0.178 AC: 44368 AN: 249110 Hom.: 4304 AF XY: 0.174 AC XY: 23448 AN XY: 134846

Gnomad AFR exome AF: 0.309

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.0869

Gnomad SAS exome AF: 0.155

Gnomad FIN exome AF: 0.236

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.173 AC: 252019 AN: 1457764 Hom.: 22566 Cov.: 31 AF XY: 0.172 AC XY: 124749 AN XY: 725258

Gnomad4 AFR exome AF: 0.309

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.0997

Gnomad4 SAS exome AF: 0.153

Gnomad4 FIN exome AF: 0.230

Gnomad4 NFE exome AF: 0.171

Gnomad4 OTH exome AF: 0.174

GnomAD4 genome AF: 0.212 AC: 32278 AN: 152154 Hom.: 3800 Cov.: 32 AF XY: 0.212 AC XY: 15806 AN XY: 74386

Gnomad4 AFR AF: 0.303

Gnomad4 AMR AF: 0.197

Gnomad4 ASJ AF: 0.108

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.153

Gnomad4 FIN AF: 0.236

Gnomad4 NFE AF: 0.176

Gnomad4 OTH AF: 0.211

Alfa AF: 0.176 Hom.: 6173

Bravo AF: 0.211

TwinsUK AF: 0.153 AC: 569

ALSPAC AF: 0.166 AC: 639

ESP6500AA AF: 0.299 AC: 1319

ESP6500EA AF: 0.171 AC: 1468

ExAC AF: 0.183 AC: 22197

Asia WGS AF: 0.192 AC: 669 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.16
Sift	Benign	0.045	D
Sift4G	Benign	0.061	T
Polyphen		0.19	B
Vest4		0.082
MPC		0.22
ClinPred		0.034	T
GERP RS		4.6
Varity_R		0.18
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

Other links and lift over

dbSNP: rs1048886; hg19: chr6-71289189; COSMIC: COSV65085544;