rs56355369

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_017636.4(TRPM4):c.1682A>C(p.Asp561Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00589 in 1,614,014 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D561E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0037 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0061 ( 52 hom. )

Consequence

TRPM4
NM_017636.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:9

Conservation

PhyloP100: 1.50

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013607472).

BP6

Variant 19-49183151-A-C is Benign according to our data. Variant chr19-49183151-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 180563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49183151-A-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00612 (8941/1461774) while in subpopulation NFE AF= 0.00733 (8152/1112010). AF 95% confidence interval is 0.0072. There are 52 homozygotes in gnomad4_exome. There are 4328 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd at 558 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM4	NM_017636.4 linkuse as main transcript	c.1682A>C	p.Asp561Ala	missense_variant	12/25	ENST00000252826.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM4	ENST00000252826.10 linkuse as main transcript	c.1682A>C	p.Asp561Ala	missense_variant	12/25	1	NM_017636.4	P1	Q8TD43-1

Frequencies

GnomAD3 genomes

AF:

0.00367

AC:

558

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00666

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00357

AC:

896

AN:

251312

Hom.:

AF XY:

0.00381

AC XY:

518

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00203

Gnomad FIN exome

AF:

0.00245

Gnomad NFE exome

AF:

0.00613

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00612

AC:

8941

AN:

1461774

Hom.:

Cov.:

AF XY:

0.00595

AC XY:

4328

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00152

Gnomad4 ASJ exome

AF:

0.000459

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00209

Gnomad4 FIN exome

AF:

0.00260

Gnomad4 NFE exome

AF:

0.00733

Gnomad4 OTH exome

AF:

0.00606

GnomAD4 genome

AF:

0.00367

AC:

558

AN:

152240

Hom.:

Cov.:

AF XY:

0.00328

AC XY:

244

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.00666

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00474

Hom.:

Bravo

AF:

0.00351

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00547

AC:

ExAC

AF:

0.00412

AC:

500

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00573

EpiControl

AF:

0.00581

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Mar 11, 2019	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	TRPM4: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -

Progressive familial heart block type IB

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Ventricular fibrillation

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

May 07, 2014

- -

TRPM4-related condition

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2019

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

Arrhythmogenic right ventricular cardiomyopathy;C0878544:Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Mar 18, 2019

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2018

This alteration is classified as 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

Uncertain

0.51

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.66

D;.

Eigen

Benign

0.074

Eigen_PC

Benign

0.0022

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.72

T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.014

T;T

MetaSVM

Uncertain

-0.23

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

0.99

N;N;N

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.8

D;D

REVEL

Uncertain

0.49

Sift

Uncertain

0.0090

D;D

Sift4G

Benign

0.063

T;T

Polyphen

0.084

B;D

Vest4

0.47

MVP

0.94

MPC

1.1

ClinPred

0.066

GERP RS

4.0

Varity_R

0.48

gMVP

0.59

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