rs71352737

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_017636.4(TRPM4):c.1575G>A(p.Trp525*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,601,502 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0016 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 5 hom. )

Consequence

TRPM4
NM_017636.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 0.670

Publications

16 publications found

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 Gene-Disease associations (from GenCC):

erythrokeratodermia variabilis et progressiva 6
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
progressive familial heart block type IB
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
erythrokeratodermia variabilis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
progressive familial heart block
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Brugada syndrome
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen

TRPM4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 19-49182889-G-A is Benign according to our data. Variant chr19-49182889-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241176.

BS2

High AC in GnomAd4 at 248 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM4	NM_017636.4 link	c.1575G>A	p.Trp525*	stop_gained	Exon 11 of 25	ENST00000252826.10	NP_060106.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM4	ENST00000252826.10 link	c.1575G>A	p.Trp525*	stop_gained	Exon 11 of 25	1	NM_017636.4	ENSP00000252826.4

Frequencies

GnomAD3 genomes

AF:

0.00163

AC:

248

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00225

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00149

AC:

341

AN:

228718

AF XY:

0.00146

show subpopulations

Gnomad AFR exome

AF:

0.000443

Gnomad AMR exome

AF:

0.000151

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00573

Gnomad NFE exome

AF:

0.00189

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00180

AC:

2607

AN:

1449182

Hom.:

Cov.:

AF XY:

0.00180

AC XY:

1294

AN XY:

719652

show subpopulations

African (AFR)

AF:

0.000362

AC:

AN:

33186

American (AMR)

AF:

0.000160

AC:

AN:

43702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25434

East Asian (EAS)

AF:

0.00

AC:

AN:

39514

South Asian (SAS)

AF:

0.000506

AC:

AN:

84964

European-Finnish (FIN)

AF:

0.00513

AC:

265

AN:

51700

Middle Eastern (MID)

AF:

0.00542

AC:

AN:

5348

European-Non Finnish (NFE)

AF:

0.00197

AC:

2177

AN:

1105672

Other (OTH)

AF:

0.00124

AC:

AN:

59662

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

151

302

454

605

756

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

240

320

400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00163

AC:

248

AN:

152320

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

135

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41580

American (AMR)

AF:

0.000457

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00659

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00225

AC:

153

AN:

68020

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00166

Hom.:

Bravo

AF:

0.00105

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00112

AC:

ExAC

AF:

0.00136

AC:

162

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TRPM4: BS1, BS2

Aug 10, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Progressive familial heart block type IB

Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 23, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with progressive familial heart block, type IB (MIM#604559). Gain of function has been reported for missense variants while there are limited reports demonstrated loss of function as a mechanism of disease for missense variants (PMIDs: 20562447, 29568272, 28315637). It should also be noted that it is currently unclear if null variants can cause disease. (I) 0107 - This gene is associated with autosomal dominant disease. There is moderate evidence for its association with progressive familial heart block, type IB (MIM#604559), and low evidence for its association with erythrokeratodermia variabilis et progressiva 6 (MIM#618531) (PanelApp Australia). (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete penetrance has been reported in families or individuals with cardiac conduction disease (PMID: 20562447). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of progressive familial heart block, type IB (MIM#604559) (gnomAD v2 and v3: 580 heterozygotes, 4 homozygotes). (SB) 0710 - Other null variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. Other NMD-predicted variants have been classified as like benign, benign or a VUS (ClinVar, CeGaT Center for Human Genetics Tuebingen personal communication). It should be noted that variants that have been classified as likely benign or benign also have a large number of heterozygotes in gnomAD v2. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as likely benign or benign by multiple clinical diagnostic laboratories although it has also been reported in individuals with sudden infant death syndrome or sudden death and considered potentially causative (PMIDs: 26350513, 28074886, 31847883). However, a recent publication from the European Society of Cardiology Council on cardiovascular genomics considers this variant to be non-pathogenic (PMID: 35089333). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

not specified

Benign:2

Oct 27, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Feb 17, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TRPM4 c.1575G>A (p.Trp525X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. It is not possible to predict the impact of this nonsense variant since Gain-of-Function is the common mechanism of disease for TRPM4 in Progressive Familial Heart Block, Type 1B (OMIM 606936). The variant allele was found at a frequency of 0.0015 in 260054 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 600 fold of the estimated maximal expected allele frequency for a pathogenic variant in TRPM4 causing Progressive Familial Heart Block Type 1B phenotype (2.5e-06), strongly suggesting that the variant is benign. Seven ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, one as likely pathogenic, three as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as benign.

Sudden cardiac death

Uncertain:1

Dec 04, 2023

Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Cardiovascular phenotype

Benign:1

Apr 03, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.0

.;.

Eigen

Benign

0.053

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.072

LIST_S2

Benign

0.0

.;.

MetaRNN

Benign

0.0

.;.

MutationAssessor

Benign

0.0

.;.

PhyloP100

0.67

PROVEAN

Benign

0.0

.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.

Sift4G

Pathogenic

0.0

.;.

Vest4

0.60

GERP RS

-0.79

Mutation Taster

=20/180

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over