6-70566945-C-G

Variant names:

• chr6-70566945-C-G
• rs553787257
• NM_145267.3:c.5C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_145267.3(SDHAF4):​c.5C>G​(p.Thr2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,432,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T2I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: SDHAF4 NM_145267.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.345
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05485332).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHAF4	NM_145267.3	MANE Select	c.5C>G	p.Thr2Ser	missense	Exon 1 of 3	NP_660310.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHAF4	ENST00000370474.4	TSL:1 MANE Select	c.5C>G	p.Thr2Ser	missense	Exon 1 of 3	ENSP00000359505.3	Q5VUM1
	SDHAF4	ENST00000468640.1	TSL:3	n.29C>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000279 AC: 4 AN: 1432926 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 709858

African (AFR) AF: 0.00 AC: 0 AN: 32882

American (AMR) AF: 0.00 AC: 0 AN: 40520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25554

East Asian (EAS) AF: 0.00 AC: 0 AN: 38266

South Asian (SAS) AF: 0.00 AC: 0 AN: 81788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00000364 AC: 4 AN: 1097784

Other (OTH) AF: 0.00 AC: 0 AN: 59258

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.6
DANN	Benign	0.64
DEOGEN2	Benign	0.0090	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.34
PROVEAN	Benign	0.31	N
REVEL	Benign	0.048
Sift	Benign	0.82	T
Sift4G	Benign	0.61	T
Polyphen		0.0030	B
Vest4		0.20
MutPred		0.20		Loss of catalytic residue at T2 (P = 0.0296)
MVP		0.12
MPC		0.080
ClinPred		0.074	T
GERP RS		2.8
PromoterAI		-0.18	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.062
gMVP		0.15
Mutation Taster		=95/5	polymorphism

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: rs553787257; hg19: chr6-71276648;