Genetic Variant TMEM26:p.Met276Val (chr10-61410603-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_178505.8(TMEM26):c.826A>G(p.Met276Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TMEM26
NM_178505.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.70

Variant links:

Genes affected

TMEM26 (HGNC:28550): (transmembrane protein 26) This gene encodes a protein containing multiple transmembrane helices. It is a selective surface protein marker of brite/beige adipocytes, which may coexist with classical brown adipocytes in brown adipose tissue. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2015]

TMEM26 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM26	NM_178505.8 link	c.826A>G	p.Met276Val	missense_variant	Exon 6 of 6	ENST00000399298.8	NP_848600.2	Q6ZUK4-1
TMEM26	NR_134507.2 link	n.1126A>G		non_coding_transcript_exon_variant	Exon 6 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMEM26	ENST00000399298.8 link	c.826A>G	p.Met276Val	missense_variant	Exon 6 of 6	1	NM_178505.8	ENSP00000382237.3	Q6ZUK4-1
TMEM26	ENST00000503886.5 link	n.826A>G		non_coding_transcript_exon_variant	Exon 6 of 7	2		ENSP00000425286.1	Q6ZUK4-1
TMEM26	ENST00000507507.1 link	n.1186A>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248568

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.826A>G (p.M276V) alteration is located in exon 6 (coding exon 6) of the TMEM26 gene. This alteration results from a A to G substitution at nucleotide position 826, causing the methionine (M) at amino acid position 276 to be replaced by a valine (V). 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

0.30

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.049

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.73

M_CAP

Benign

0.0050

MetaRNN

Uncertain

0.45

MetaSVM

Benign

-0.48

MutationAssessor

Uncertain

2.7

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.99

REVEL

Benign

0.15

Sift

Uncertain

0.022

Sift4G

Uncertain

0.021

Polyphen

0.16

Vest4

0.55

MutPred

0.66

Gain of sheet (P = 0.0827);

MVP

0.25

MPC

0.28

ClinPred

0.54

GERP RS

6.0

Varity_R

0.29

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over