Genetic Variant TMEM176A:p.Leu184Pro (chr7-150803828-T-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_018487.3(TMEM176A):c.551T>C(p.Leu184Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,613,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

TMEM176A
NM_018487.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.822

Variant links:

Genes affected

TMEM176A (HGNC:24930): (transmembrane protein 176A) Predicted to be involved in negative regulation of dendritic cell differentiation. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM176A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM176A	NM_018487.3 link	c.551T>C	p.Leu184Pro	missense_variant	Exon 5 of 7	ENST00000004103.8	NP_060957.2	Q96HP8A0A090N8H6
TMEM176A	XM_011516376.4 link	c.602T>C	p.Leu201Pro	missense_variant	Exon 5 of 7		XP_011514678.1
TMEM176A	XM_011516378.3 link	c.602T>C	p.Leu201Pro	missense_variant	Exon 5 of 6		XP_011514680.1
TMEM176A	XM_024446824.2 link	c.551T>C	p.Leu184Pro	missense_variant	Exon 5 of 6		XP_024302592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM176A	ENST00000004103.8 link	c.551T>C	p.Leu184Pro	missense_variant	Exon 5 of 7	1	NM_018487.3	ENSP00000004103.3		Q96HP8

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00316

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000759

AC:

AN:

250176

Hom.:

AF XY:

0.0000813

AC XY:

AN XY:

135262

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.0000997

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000983

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000885

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000506

AC:

AN:

1461444

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727002

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000103

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000902

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.551T>C (p.L184P) alteration is located in exon 5 (coding exon 4) of the TMEM176A gene. This alteration results from a T to C substitution at nucleotide position 551, causing the leucine (L) at amino acid position 184 to be replaced by a proline (P). 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

Pathogenic

0.57

BayesDel_addAF

Benign

0.0087

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.019

T;T;.;T;.

Eigen

Benign

0.12

Eigen_PC

Benign

-0.087

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.48

.;T;.;T;T

M_CAP

Benign

0.013

MetaRNN

Pathogenic

0.95

D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;M;.;.;.

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.0

D;D;D;D;.

REVEL

Benign

0.27

Sift

Uncertain

0.0010

D;D;D;D;.

Sift4G

Uncertain

0.0020

D;D;D;D;.

Polyphen

1.0

D;D;.;.;.

Vest4

0.85

MutPred

0.89

Loss of stability (P = 0.0228);Loss of stability (P = 0.0228);.;.;.;

MVP

0.15

MPC

1.4

ClinPred

0.39

GERP RS

3.5

Varity_R

0.87

gMVP

0.80

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over