15-76192043-C-T

Variant names:

• chr15-76192043-C-T
• rs753844829
• NM_152335.5:c.820C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152335.5(TMEM266):​c.820C>T​(p.Gln274*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000143 in 1,399,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMEM266 NM_152335.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.18
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.820C>T	p.Gln274*	stop_gained	Exon 9 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.820C>T	p.Gln274*	stop_gained	Exon 9 of 11	ENSP00000373594.4
	TMEM266	ENST00000561302.6	TSL:1	n.*323C>T		non_coding_transcript_exon	Exon 8 of 11	ENSP00000453957.2	H0YNC9
	TMEM266	ENST00000561302.6	TSL:1	n.*323C>T		3_prime_UTR	Exon 8 of 11	ENSP00000453957.2	H0YNC9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399806 Hom.: 0 Cov.: 31 AF XY: 0.00000288 AC XY: 2 AN XY: 694272

African (AFR) AF: 0.00 AC: 0 AN: 28582

American (AMR) AF: 0.00 AC: 0 AN: 37160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23876

East Asian (EAS) AF: 0.00 AC: 0 AN: 34196

South Asian (SAS) AF: 0.00 AC: 0 AN: 79970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4004

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1087854

Other (OTH) AF: 0.00 AC: 0 AN: 57568

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		5.2
Vest4		0.33
GERP RS		3.6
Mutation Taster		=6/194	disease causing (fs/PTC)

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: rs753844829; hg19: chr15-76484384;