rs754625848

Positions:

• chr19-49166190-C-CG

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_017636.4(TRPM4):​c.247dup​(p.Ala83GlyfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000771 in 1,607,484 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T81T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: TRPM4 NM_017636.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.0840

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 -4 ACMG points.

• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM4	NM_017636.4	c.247dup	p.Ala83GlyfsTer13	frameshift_variant	3/25	ENST00000252826.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM4	ENST00000252826.10	c.247dup	p.Ala83GlyfsTer13	frameshift_variant	3/25	1	NM_017636.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152150 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000426 AC: 10 AN: 234470 Hom.: 0 AF XY: 0.0000627 AC XY: 8 AN XY: 127608

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000604

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000687

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000571

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000783 AC: 114 AN: 1455216 Hom.: 0 Cov.: 31 AF XY: 0.0000843 AC XY: 61 AN XY: 723340

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000456

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000820

Gnomad4 OTH exome AF: 0.000200

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152268 Hom.: 0 Cov.: 31 AF XY: 0.0000940 AC XY: 7 AN XY: 74452

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000491

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

AiLife Diagnostics, AiLife Diagnostics

Nov 18, 2021

- -

Progressive familial heart block type IB Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 14, 2023

This sequence change creates a premature translational stop signal (p.Ala83Glyfs*13) in the TRPM4 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TRPM4 cause disease. This variant is present in population databases (rs754625848, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with sudden infant death syndrome, atrial fibrillation and dilated cardiomyopathy (PMID: 28074886, 34495297, 35288587). ClinVar contains an entry for this variant (Variation ID: 518703). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2023

The c.247dupG variant, located in coding exon 3 of the TRPM4 gene, results from a duplication of one at nucleotide position 247, causing a translational frameshift with a predicted alternate stop codon (p.A83Gfs*13). This alteration was found by whole exome sequencing in one case of sudden infant death syndrome (Neubauer J et al. Eur. J. Hum. Genet., 2017 Apr;25:404-409). This alteration has also been seen in an atrial fibrillation cohort and a cardiomyopathy cohort (Yoneda ZT et al. JAMA Cardiol, 2021 Dec;6:1371-1379; Lesurf R et al. NPJ Genom Med, 2022 Mar;7:18). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of TRPM4 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs754625848; hg19: chr19-49669447;