Genetic Variant TMEM266:p.Ala275Gly (chr15-76192047-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152335.5(TMEM266):c.824C>G(p.Ala275Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000216 in 1,391,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A275D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

TMEM266
NM_152335.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.00

Publications

0 publications found

Variant links:

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]

TMEM266 links:

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)

ETFA links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1744366).

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.824C>G	p.Ala275Gly	missense	Exon 9 of 11	NP_689548.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM266	ENST00000388942.9	TSL:5 MANE Select	c.824C>G	p.Ala275Gly	missense	Exon 9 of 11	ENSP00000373594.4
TMEM266	ENST00000561302.6	TSL:1	n.*327C>G		non_coding_transcript_exon	Exon 8 of 11	ENSP00000453957.2	H0YNC9
TMEM266	ENST00000561302.6	TSL:1	n.*327C>G		3_prime_UTR	Exon 8 of 11	ENSP00000453957.2	H0YNC9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000216

AC:

AN:

1391808

Hom.:

Cov.:

AF XY:

0.00000435

AC XY:

AN XY:

689868

show subpopulations

African (AFR)

AF:

0.0000708

AC:

AN:

28262

American (AMR)

AF:

0.00

AC:

AN:

35674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23548

East Asian (EAS)

AF:

0.00

AC:

AN:

33780

South Asian (SAS)

AF:

0.0000127

AC:

AN:

78842

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46240

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3980

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1084256

Other (OTH)

AF:

0.00

AC:

AN:

57226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0038

Eigen

Benign

0.085

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.048

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.96

PhyloP100

4.0

PROVEAN

Benign

-0.91

REVEL

Benign

0.044

Sift

Benign

0.051

Sift4G

Benign

0.18

Polyphen

0.23

Vest4

0.24

MutPred

0.21

Gain of loop (P = 0.0851)

MVP

0.50

MPC

0.23

ClinPred

0.78

GERP RS

2.7

Varity_R

0.12

gMVP

0.32

Mutation Taster

=91/9

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over