Genetic Variant TMEM266:p.Pro290Leu (chr15-76192068-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000388942.8(TMEM266):c.869C>T(p.Pro290Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000121 in 1,485,952 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

TMEM266
ENST00000388942.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.54

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21003702).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
TMEM266	NM_152335.5 link	c.845C>T	p.Pro282Leu	missense_variant	Exon 9 of 11	NP_689548.3	Q2M3C6
TMEM266	XM_017021915.2 link	c.869C>T	p.Pro290Leu	missense_variant	Exon 11 of 13	XP_016877404.1	Q2M3C6-1
TMEM266	XM_047432151.1 link	c.869C>T	p.Pro290Leu	missense_variant	Exon 11 of 13	XP_047288107.1
TMEM266	XM_005254160.4 link	c.317C>T	p.Pro106Leu	missense_variant	Exon 7 of 9	XP_005254217.1	Q2M3C6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM266	ENST00000388942.8 link	c.869C>T	p.Pro290Leu	missense_variant	Exon 9 of 11	5	NM_152335.3	ENSP00000373594.4		Q2M3C6-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000120

AC:

AN:

1333736

Hom.:

Cov.:

AF XY:

0.0000168

AC XY:

AN XY:

656064

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000226

Gnomad4 ASJ exome

AF:

0.0000470

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000284

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000284

Gnomad4 OTH exome

AF:

0.0000548

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000582

Hom.:

Bravo

AF:

0.0000264

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0082

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.088

MetaRNN

Benign

0.21

MetaSVM

Benign

-1.1

PROVEAN

Benign

-0.62

REVEL

Benign

0.057

Sift

Uncertain

0.014

Sift4G

Benign

0.10

Polyphen

0.88

Vest4

0.20

MutPred

0.30

Gain of MoRF binding (P = 0.0336);

MVP

0.77

MPC

0.65

ClinPred

0.75

GERP RS

3.4

Varity_R

0.094

gMVP

0.38

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over