15-76203986-G-T

Variant names:

• chr15-76203986-G-T
• rs749721963
• ENST00000388942.8:c.1267G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000388942.8(TMEM266):​c.1267G>T​(p.Gly423Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 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)
• Consequence: TMEM266 ENST00000388942.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.420

Genes affected

TMEM266 (HGNC:26763): (transmembrane protein 266) Enables protein homodimerization activity. Predicted to be involved in transmembrane transport. Located in cytosol; dendrite; and plasma membrane. Is integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ETFA (HGNC:3481): (electron transfer flavoprotein subunit alpha) ETFA participates in catalyzing the initial step of the mitochondrial fatty acid beta-oxidation. It shuttles electrons between primary flavoprotein dehydrogenases and the membrane-bound electron transfer flavoprotein ubiquinone oxidoreductase. Defects in electron-transfer-flavoprotein have been implicated in type II glutaricaciduria in which multiple acyl-CoA dehydrogenase deficiencies result in large excretion of glutaric, lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05821529).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM266	NM_152335.5	c.1243G>T	p.Gly415Cys	missense_variant	Exon 11 of 11		NP_689548.3
TMEM266	XM_017021915.2	c.1267G>T	p.Gly423Cys	missense_variant	Exon 13 of 13		XP_016877404.1
TMEM266	XM_047432151.1	c.1267G>T	p.Gly423Cys	missense_variant	Exon 13 of 13		XP_047288107.1
TMEM266	XM_005254160.4	c.715G>T	p.Gly239Cys	missense_variant	Exon 9 of 9		XP_005254217.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM266	ENST00000388942.8	c.1267G>T	p.Gly423Cys	missense_variant	Exon 11 of 11	5	NM_152335.3	ENSP00000373594.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000278 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1267G>T (p.G423C) alteration is located in exon 11 (coding exon 10) of the TMEM266 gene. This alteration results from a G to T substitution at nucleotide position 1267, causing the glycine (G) at amino acid position 423 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.1
DANN	Benign	0.95
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.040
Sift	Benign	0.23	T
Sift4G	Benign	0.20	T
Polyphen		0.0010	B
Vest4		0.21
MutPred		0.13		Gain of catalytic residue at P422 (P = 0.0188);
MVP		0.19
MPC		0.43
ClinPred		0.041	T
GERP RS		-5.5
Varity_R		0.088
gMVP		0.098

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

Publications

LitVar

Other links and lift over

dbSNP: rs749721963; hg19: chr15-76496327;