15-76160103-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000388942.9(TMEM266):c.367G>T(p.Ala123Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM266 ENST00000388942.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.23

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27184695).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM266	NM_152335.5	c.367G>T	p.Ala123Ser	missense_variant	5/11	ENST00000388942.9
TMEM266	XM_047432151.1	c.391G>T	p.Ala131Ser	missense_variant	7/13
TMEM266	XM_017021915.2	c.391G>T	p.Ala131Ser	missense_variant	7/13
TMEM266	XM_005254160.4	c.-162G>T		5_prime_UTR_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM266	ENST00000388942.9	c.367G>T	p.Ala123Ser	missense_variant	5/11	5	NM_152335.5	P1
TMEM266	ENST00000561302.6	c.212G>T	p.Arg71Leu	missense_variant, NMD_transcript_variant	4/11	1
TMEM266	ENST00000484722.6	c.261G>T	p.Ala87=	synonymous_variant, NMD_transcript_variant	5/11	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2023

The c.391G>T (p.A131S) alteration is located in exon 5 (coding exon 4) of the TMEM266 gene. This alteration results from a G to T substitution at nucleotide position 391, causing the alanine (A) at amino acid position 131 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0042	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	0.56	D
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-0.26	N
REVEL	Uncertain	0.46
Sift	Benign	0.15	T
Sift4G	Benign	0.10	T
Polyphen		0.73	P
Vest4		0.41
MutPred		0.53		Loss of helix (P = 0.0444);
MVP		0.92
MPC		0.28
ClinPred		0.88	D
GERP RS		4.8
Varity_R		0.087
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-76452444;