chr15-76203986-G-T

Variant names:

• chr15-76203986-G-T
• rs749721963
• NM_152335.5:c.1243G>T

Variant summary

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

The NM_152335.5(TMEM266):​c.1243G>T​(p.Gly415Cys) 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. 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)
• Consequence: TMEM266 NM_152335.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.420
• Publications: 1 publications found

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]

ETFA Gene-Disease associations (from GenCC):

• multiple acyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)

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=0.05821529).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152335.5. 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
	TMEM266	NM_152335.5	MANE Select	c.1243G>T	p.Gly415Cys	missense	Exon 11 of 11	NP_689548.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM266	ENST00000388942.9	TSL:5 MANE Select	c.1243G>T	p.Gly415Cys	missense	Exon 11 of 11	ENSP00000373594.4
	TMEM266	ENST00000561302.6	TSL:1	n.*746G>T		non_coding_transcript_exon	Exon 10 of 11	ENSP00000453957.2	H0YNC9
	TMEM266	ENST00000561302.6	TSL:1	n.*746G>T		3_prime_UTR	Exon 10 of 11	ENSP00000453957.2	H0YNC9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000204 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

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	0.077
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
PhyloP100		0.42
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

Other links and lift over

dbSNP: rs749721963; hg19: chr15-76496327;