NM_145267.3:c.16C>T

Variant names:

• chr6-70566956-C-T
• NM_145267.3:c.16C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145267.3(SDHAF4):​c.16C>T​(p.Leu6Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,437,734 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: SDHAF4 NM_145267.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.410
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06855452).

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.16C>T	p.Leu6Phe	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.16C>T	p.Leu6Phe	missense	Exon 1 of 3	ENSP00000359505.3	Q5VUM1
	SDHAF4	ENST00000468640.1	TSL:3	n.40C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000348 AC: 5 AN: 1437734 Hom.: 0 Cov.: 31 AF XY: 0.00000281 AC XY: 2 AN XY: 712628

African (AFR) AF: 0.00 AC: 0 AN: 33010

American (AMR) AF: 0.00 AC: 0 AN: 41216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25630

East Asian (EAS) AF: 0.00 AC: 0 AN: 38556

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 82272

European-Finnish (FIN) AF: 0.0000195 AC: 1 AN: 51408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1100510

Other (OTH) AF: 0.0000168 AC: 1 AN: 59436

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	12
DANN	Benign	0.77
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.41
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.028
Sift	Benign	0.16	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.011	B
Vest4		0.21
MutPred		0.23		Loss of catalytic residue at L6 (P = 0.007)
MVP		0.088
MPC		0.099
ClinPred		0.055	T
GERP RS		-0.30
PromoterAI		-0.13	Neutral
Varity_R		0.061
gMVP		0.14
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr6-71276659;