rs142312281

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_017636.4(TRPM4):c.1376G>A(p.Arg459His) variant causes a missense change. The variant allele was found at a frequency of 0.000142 in 1,614,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R459C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00075 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

TRPM4
NM_017636.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 6.13

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.088492066).

BP6

Variant 19-49182690-G-A is Benign according to our data. Variant chr19-49182690-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 468927.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

BS2

High AC in GnomAd at 113 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM4	NM_017636.4 linkuse as main transcript	c.1376G>A	p.Arg459His	missense_variant	11/25	ENST00000252826.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM4	ENST00000252826.10 linkuse as main transcript	c.1376G>A	p.Arg459His	missense_variant	11/25	1	NM_017636.4	P1	Q8TD43-1

Frequencies

GnomAD3 genomes

AF:

0.000743

AC:

113

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000247

AC:

AN:

251030

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135740

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000598

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000794

AC:

116

AN:

1461844

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00221

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000748

AC:

114

AN:

152306

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00245

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000990

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000272

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 12, 2023

Identified in a patient with reported history of bradycardia, failure to thrive, hypoxemia, hypsarrhythmia, PFO, seizures, and tachycardia (Ji et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30755392) -

TRPM4-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Patent foramen ovale;C0036572:Seizure;C0039231:Tachycardia;C0428977:Bradycardia;C0684276:Hypsarrhythmia;C0700292:Hypoxemia;C2315100:Failure to thrive

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

- -

Progressive familial heart block type IB

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 03, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2019

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

Benign

0.24

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

D;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

D;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.088

T;T

MetaSVM

Benign

-0.39

MutationAssessor

Pathogenic

3.3

M;M

MutationTaster

Benign

0.96

D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.3

D;D

REVEL

Benign

0.26

Sift

Uncertain

0.023

D;D

Sift4G

Uncertain

0.016

D;D

Polyphen

1.0

D;D

Vest4

0.64

MVP

0.87

MPC

0.80

ClinPred

0.13

GERP RS

4.2

Varity_R

0.17

gMVP

0.79

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