chr6-70579486-A-G

Variant names:

• chr6-70579486-A-G
• rs1048886
• NM_145267.3:c.137A>G

Variant summary

Our verdict is Benign. The variant received -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. 11/19 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 0.21 (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
• Publications: 81 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145267.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHAF4	NM_145267.3	MANE Select	c.137A>G	p.Gln46Arg	missense	Exon 2 of 3	NP_660310.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHAF4	ENST00000370474.4	TSL:1 MANE Select	c.137A>G	p.Gln46Arg	missense	Exon 2 of 3	ENSP00000359505.3

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

GnomAD2 exomes AF: 0.178 AC: 44368 AN: 249110 AF XY: 0.174

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 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

African (AFR) AF: 0.309 AC: 10273 AN: 33256

American (AMR) AF: 0.184 AC: 8127 AN: 44234

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2835 AN: 26064

East Asian (EAS) AF: 0.0997 AC: 3944 AN: 39544

South Asian (SAS) AF: 0.153 AC: 13055 AN: 85572

European-Finnish (FIN) AF: 0.230 AC: 12245 AN: 53270

Middle Eastern (MID) AF: 0.212 AC: 1220 AN: 5756

European-Non Finnish (NFE) AF: 0.171 AC: 189820 AN: 1109882

Other (OTH) AF: 0.174 AC: 10500 AN: 60186

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

African (AFR) AF: 0.303 AC: 12585 AN: 41492

American (AMR) AF: 0.197 AC: 3006 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 374 AN: 3472

East Asian (EAS) AF: 0.101 AC: 524 AN: 5180

South Asian (SAS) AF: 0.153 AC: 736 AN: 4824

European-Finnish (FIN) AF: 0.236 AC: 2500 AN: 10590

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.176 AC: 11975 AN: 67994

Other (OTH) AF: 0.211 AC: 446 AN: 2110

Alfa AF: 0.181 Hom.: 12611

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 v4.9

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
PhyloP100		4.8
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
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

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