rs2469564

Variant names:

• chr15-76197614-A-G
• rs2469564
• ENST00000388942.9:c.935-4588A>G

Variant summary

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

The ENST00000388942.9(TMEM266):​c.935-4588A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 152,274 control chromosomes in the GnomAD database, including 1,658 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 0.14 (1658 hom., cov: 34)
• Consequence: TMEM266 ENST00000388942.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0990
• Publications: 2 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM266	NM_152335.5	c.935-4588A>G		intron_variant	Intron 9 of 10		NP_689548.3
TMEM266	XM_017021915.2	c.959-4588A>G		intron_variant	Intron 11 of 12		XP_016877404.1
TMEM266	XM_047432151.1	c.959-4588A>G		intron_variant	Intron 11 of 12		XP_047288107.1
TMEM266	XM_005254160.4	c.407-4588A>G		intron_variant	Intron 7 of 8		XP_005254217.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM266	ENST00000388942.9	c.935-4588A>G		intron_variant	Intron 9 of 10	5		ENSP00000373594.4

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20550 AN: 152154 Hom.: 1651 Cov.: 34

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0767

Gnomad ASJ AF: 0.0749

Gnomad EAS AF: 0.0504

Gnomad SAS AF: 0.0747

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.120

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

GnomAD4 genome AF: 0.135 AC: 20578 AN: 152274 Hom.: 1658 Cov.: 34 AF XY: 0.135 AC XY: 10055 AN XY: 74462

African (AFR) AF: 0.224 AC: 9297 AN: 41546

American (AMR) AF: 0.0766 AC: 1172 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0749 AC: 260 AN: 3472

East Asian (EAS) AF: 0.0497 AC: 257 AN: 5170

South Asian (SAS) AF: 0.0748 AC: 361 AN: 4828

European-Finnish (FIN) AF: 0.139 AC: 1471 AN: 10614

Middle Eastern (MID) AF: 0.0616 AC: 18 AN: 292

European-Non Finnish (NFE) AF: 0.110 AC: 7467 AN: 68020

Other (OTH) AF: 0.125 AC: 264 AN: 2114

Alfa AF: 0.123 Hom.: 237

Bravo AF: 0.133

Asia WGS AF: 0.0840 AC: 294 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.4
DANN	Benign	0.76
PhyloP100		0.099
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2469564; hg19: chr15-76489955;