Variant 4-38988956-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000381938.4(TMEM156):c.634A>T(p.Met212Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,611,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M212T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

TMEM156
ENST00000381938.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.598

Variant links:

Genes affected

TMEM156 (HGNC:26260): (transmembrane protein 156) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM156 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04665941).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM156	NM_024943.3 linkuse as main transcript	c.634A>T	p.Met212Leu	missense_variant	4/7	ENST00000381938.4	NP_079219.1	Q8N614A1MMZ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM156	ENST00000381938.4 linkuse as main transcript	c.634A>T	p.Met212Leu	missense_variant	4/7	1	NM_024943.3	ENSP00000371364.3		Q8N614

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

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

GnomAD3 exomes

AF:

0.0000560

AC:

AN:

250140

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135364

show subpopulations

Gnomad AFR exome

AF:

0.000684

Gnomad AMR exome

AF:

0.0000872

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1459220

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726072

show subpopulations

Gnomad4 AFR exome

AF:

0.000480

Gnomad4 AMR exome

AF:

0.0000449

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:

9.01e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000190

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000698

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:

0.000142

Hom.:

Bravo

AF:

0.000193

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2024

The c.634A>T (p.M212L) alteration is located in exon 4 (coding exon 4) of the TMEM156 gene. This alteration results from a A to T substitution at nucleotide position 634, causing the methionine (M) at amino acid position 212 to be replaced by a leucine (L). 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

0.13

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.0034

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.082

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.65

M_CAP

Benign

0.0059

MetaRNN

Benign

0.047

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

0.97

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.6

REVEL

Benign

0.041

Sift

Benign

0.075

Sift4G

Benign

0.19

Polyphen

0.59

Vest4

0.26

MutPred

0.29

Gain of methylation at K213 (P = 0.0806);

MVP

0.081

MPC

0.046

ClinPred

0.059

GERP RS

4.3

Varity_R

0.13

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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