Variant 4-955426-G-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 NM_032326.4(TMEM175):c.649G>A(p.Val217Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000344 in 1,614,138 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 1 hom. )

Consequence

TMEM175
NM_032326.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.82

Variant links:

Genes affected

TMEM175 (HGNC:28709): (transmembrane protein 175) Enables potassium ion leak channel activity. Involved in potassium ion transmembrane transport. Located in endosome and lysosome. Is integral component of endosome membrane and integral component of lysosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM175 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=0.05273381).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM175	NM_032326.4 linkuse as main transcript	c.649G>A	p.Val217Ile	missense_variant	9/11	ENST00000264771.9	NP_115702.1	Q9BSA9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM175	ENST00000264771.9 linkuse as main transcript	c.649G>A	p.Val217Ile	missense_variant	9/11	1	NM_032326.4	ENSP00000264771.4		Q9BSA9-1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000115

AC:

AN:

251116

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135816

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:

0.000255

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000365

AC:

533

AN:

1461790

Hom.:

Cov.:

AF XY:

0.000355

AC XY:

258

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.000469

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000151

AC:

AN:

152348

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000268

Hom.:

Bravo

AF:

0.000162

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

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

Dec 01, 2024

The c.649G>A (p.V217I) alteration is located in exon 9 (coding exon 8) of the TMEM175 gene. This alteration results from a G to A substitution at nucleotide position 649, causing the valine (V) at amino acid position 217 to be replaced by an isoleucine (I). 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

0.099

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.53

CADD

Benign

9.3

DANN

Benign

0.90

DEOGEN2

Benign

0.0028

T;T;.;.;.;T;.

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.68

T;T;T;.;T;T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.053

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;.;.;.;.;.;.

PrimateAI

Benign

0.36

PROVEAN

Benign

0.24

N;N;N;N;N;N;.

REVEL

Benign

0.067

Sift

Benign

0.21

T;T;T;T;T;T;.

Sift4G

Benign

0.15

T;T;D;T;T;T;T

Polyphen

0.015

B;.;.;.;B;B;.

Vest4

0.24

MVP

0.067

MPC

0.13

ClinPred

0.037

GERP RS

1.5

Varity_R

0.016

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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