6-70588652-A-T

Variant names:

• chr6-70588652-A-T
• rs767309184
• NM_145267.3:c.255A>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_145267.3(SDHAF4):​c.255A>T​(p.Lys85Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000152 in 1,447,528 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: SDHAF4 NM_145267.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.931

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38855755).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHAF4	NM_145267.3	c.255A>T	p.Lys85Asn	missense_variant	Exon 3 of 3	ENST00000370474.4	NP_660310.2
SDHAF4	XM_047418210.1	c.217+9086A>T		intron_variant	Intron 2 of 2		XP_047274166.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHAF4	ENST00000370474.4	c.255A>T	p.Lys85Asn	missense_variant	Exon 3 of 3	1	NM_145267.3	ENSP00000359505.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000152 AC: 22 AN: 1447528 Hom.: 0 Cov.: 29 AF XY: 0.0000139 AC XY: 10 AN XY: 720158

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: 0.0000154

Gnomad4 OTH exome AF: 0.0000840

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-1.1	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.12
Sift	Benign	0.098	T
Sift4G	Benign	0.15	T
Polyphen		0.99	D
Vest4		0.20
MutPred		0.37		Loss of ubiquitination at K85 (P = 0.0043);
MVP		0.60
MPC		0.50
ClinPred		0.94	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.49

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: rs767309184; hg19: chr6-71298355;