NM_017636.4:c.1575G>A

Variant names:

• chr19-49182889-G-A
• rs71352737
• NM_017636.4:c.1575G>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.670

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]

ACMG classification

Verdict is Likely_benign. Variant got -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 id is 241176.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=4, Uncertain_significance=1}. Variant chr19-49182889-G-A is described in Lovd as [Likely_benign]. Variant chr19-49182889-G-A is described in Lovd as [Likely_pathogenic].
• 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	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	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.: 2 Cov.: 32

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

GnomAD3 exomes AF: 0.00149 AC: 341 AN: 228718 Hom.: 1 AF XY: 0.00146 AC XY: 184 AN XY: 125860

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 SAS exome AF: 0.000487

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.: 5 Cov.: 33 AF XY: 0.00180 AC XY: 1294 AN XY: 719652

Gnomad4 AFR exome AF: 0.000362

Gnomad4 AMR exome AF: 0.000160

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000506

Gnomad4 FIN exome AF: 0.00513

Gnomad4 NFE exome AF: 0.00197

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00163 AC: 248 AN: 152320 Hom.: 2 Cov.: 32 AF XY: 0.00181 AC XY: 135 AN XY: 74484

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00659

Gnomad4 NFE AF: 0.00225

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.00105

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00112 AC: 9

ExAC AF: 0.00136 AC: 162

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Aug 10, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

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

- -

-

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

- -

-

Clinical Genetics, Academic Medical Center

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 -

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. -

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 -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

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. -

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. -

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	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	32
DANN	Uncertain	0.97
Eigen	Benign	0.053
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.072	N
Vest4		0.60
GERP RS		-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

Other links and lift over

dbSNP: rs71352737; hg19: chr19-49686146;