15-76204113-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The ENST00000388942.9(TMEM266):c.1370G>A(p.Arg457Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,612,768 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: TMEM266 ENST00000388942.9 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.281

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01902473).
• BP6: Variant 15-76204113-G-A is Benign according to our data. Variant chr15-76204113-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2394641.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM266	NM_152335.5	c.1370G>A	p.Arg457Gln	missense_variant	11/11	ENST00000388942.9
TMEM266	XM_047432151.1	c.1394G>A	p.Arg465Gln	missense_variant	13/13
TMEM266	XM_017021915.2	c.1394G>A	p.Arg465Gln	missense_variant	13/13
TMEM266	XM_005254160.4	c.842G>A	p.Arg281Gln	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM266	ENST00000388942.9	c.1370G>A	p.Arg457Gln	missense_variant	11/11	5	NM_152335.5	P1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000101 AC: 25 AN: 247720 Hom.: 0 AF XY: 0.0000742 AC XY: 10 AN XY: 134822

Gnomad AFR exome AF: 0.0000658

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000718

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.0000445 AC: 65 AN: 1460664 Hom.: 0 Cov.: 32 AF XY: 0.0000468 AC XY: 34 AN XY: 726618

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000380

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74292

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.0000495 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	1.4
Dann	Benign	0.83
DEOGEN2	Benign	0.0020	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.019
Sift	Benign	0.35	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.022
MVP		0.12
MPC		0.24
ClinPred		0.036	T
GERP RS		-9.7
Varity_R		0.028
gMVP		0.090

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: rs774278839; hg19: chr15-76496454; COSMIC: COSV101189552;