rs2255408

Variant names:

• chr15-76210954-A-C
• rs2255408
• ENST00000561302.6:n.*922+6792A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000561302.6(TMEM266):​n.*922+6792A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 150,960 control chromosomes in the GnomAD database, including 3,737 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (3737 hom., cov: 32)
• Consequence: TMEM266 ENST00000561302.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0230
• Publications: 10 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM266	ENST00000561302.6	n.*922+6792A>C		intron_variant	Intron 10 of 10	1		ENSP00000453957.2
ETFA	ENST00000690610.1	n.*1158+3571T>G		intron_variant	Intron 13 of 14			ENSP00000510473.1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 31897 AN: 150842 Hom.: 3729 Cov.: 32

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.0517

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.182

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.202

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.212 AC: 31941 AN: 150960 Hom.: 3737 Cov.: 32 AF XY: 0.212 AC XY: 15618 AN XY: 73828

African (AFR) AF: 0.314 AC: 12683 AN: 40428

American (AMR) AF: 0.156 AC: 2379 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 727 AN: 3458

East Asian (EAS) AF: 0.0512 AC: 265 AN: 5174

South Asian (SAS) AF: 0.129 AC: 623 AN: 4828

European-Finnish (FIN) AF: 0.201 AC: 2125 AN: 10578

Middle Eastern (MID) AF: 0.178 AC: 52 AN: 292

European-Non Finnish (NFE) AF: 0.186 AC: 12640 AN: 67972

Other (OTH) AF: 0.204 AC: 427 AN: 2096

Alfa AF: 0.188 Hom.: 2068

Bravo AF: 0.210

Asia WGS AF: 0.117 AC: 408 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.3
DANN	Benign	0.72
PhyloP100		-0.023

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2255408; hg19: chr15-76503295;