rs769917929

chr19-49196483-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4 BP6 BS2

The NM_017636.4(TRPM4):c.2254C>T(p.Gln752Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00037 in 1,555,324 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a pathogenic 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 0.00037 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00037 (4 hom.)
• Consequence: TRPM4 NM_017636.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.831

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 -3 ACMG points.

• PM4: Stoplost variant in NM_017636.4 Downstream stopcodon found after 1239 codons.
• BP6: Variant 19-49196483-C-T is Benign according to our data. Variant chr19-49196483-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 373748.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3, Benign=1}.
• BS2: High AC in GnomAd at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM4	NM_017636.4	c.2254C>T	p.Gln752Ter	stop_gained	17/25	ENST00000252826.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM4	ENST00000252826.10	c.2254C>T	p.Gln752Ter	stop_gained	17/25	1	NM_017636.4	P1

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152160 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000753 AC: 118 AN: 156796 Hom.: 0 AF XY: 0.000689 AC XY: 59 AN XY: 85660

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000388

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000370 AC: 519 AN: 1403164 Hom.: 4 Cov.: 32 AF XY: 0.000363 AC XY: 252 AN XY: 693412

Gnomad4 AFR exome AF: 0.0000621

Gnomad4 AMR exome AF: 0.0000271

Gnomad4 ASJ exome AF: 0.0133

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000106

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.000375 AC: 57 AN: 152160 Hom.: 1 Cov.: 31 AF XY: 0.000363 AC XY: 27 AN XY: 74344

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00174 Hom.: 1

Bravo AF: 0.000412

ExAC AF: 0.000310 AC: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Progressive familial heart block type IB Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 09, 2019	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 09, 2016

A variant of uncertain significance has been identified in the TRPM4 gene. The Q752X variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. Q752X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Nevertheless, only one nonsense variant (W525X) has been reported in HGMD in association with sudden unexpected death in infancy (Stenson et al., 2014), and haploinsufficiency is not a well-established disease mechanism for the TRPM4 gene. Moreover, the Exome Aggregation Consortium reports Q752X was observed in 26/5080 (0.5%) alleles from individuals of European (Non-Finnish) background, indicating it may be a rare benign variant in these populations. -

TRPM4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2022

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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2023

TRPM4: BS2 -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2018

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	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Benign	0.15
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.31	N
MutationTaster	Benign	1.0	A;A;D
Vest4		0.41
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs769917929; hg19: chr19-49699740;