rs148763371

Positions:

chr19-49172040-T-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS2

The NM_017636.4(TRPM4):c.1082T>G(p.Leu361Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,613,952 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

TRPM4
NM_017636.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 3.21

Variant links:

Genes affected

TRPM4 (HGNC:17993): (transient receptor potential cation channel subfamily M member 4) The protein encoded by this gene is a calcium-activated nonselective ion channel that mediates transport of monovalent cations across membranes, thereby depolarizing the membrane. The activity of the encoded protein increases with increasing intracellular calcium concentration, but this channel does not transport calcium. [provided by RefSeq, Mar 2016]

TRPM4 links:

TRPM4 (HGNC:):

TRPM4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.85

BP6

Variant 19-49172040-T-G is Benign according to our data. Variant chr19-49172040-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180562.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM4	NM_017636.4 linkuse as main transcript	c.1082T>G	p.Leu361Arg	missense_variant	9/25	ENST00000252826.10	NP_060106.2	Q8TD43-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM4	ENST00000252826.10 linkuse as main transcript	c.1082T>G	p.Leu361Arg	missense_variant	9/25	1	NM_017636.4	ENSP00000252826.4		Q8TD43-1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000302

AC:

AN:

251474

Hom.:

AF XY:

0.000331

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000343

Gnomad OTH exome

AF:

0.000977

GnomAD4 exome

AF:

0.000256

AC:

374

AN:

1461820

Hom.:

Cov.:

AF XY:

0.000276

AC XY:

201

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000402

Gnomad4 ASJ exome

AF:

0.00107

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.000618

Gnomad4 NFE exome

AF:

0.000225

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000177

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000351

Hom.:

Bravo

AF:

0.000227

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000346

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2019	Has not been previously published as pathogenic or benign to our knowledge; Observed in 82/277,138 (0.0296%) global alleles, including 13/10,152 (0.1281%) alleles from individuals of Ashkenazi Jewish background, in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar (ClinVar Variant ID# 180562; Landrum et al., 2016) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	TRPM4: BS2 -

Long QT syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Oct 30, 2014

- -

Progressive familial heart block type IB

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.38

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.81

T;T

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Uncertain

0.74

MutationAssessor

Uncertain

2.8

M;M

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.3

D;D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.94

MVP

0.91

MPC

1.1

ClinPred

0.22

GERP RS

4.8

Varity_R

0.93

gMVP

0.90

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