rs754625848

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 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

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.0840
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 Protein UniProt
TRPM4NM_017636.4 linkuse as main transcriptc.247dup p.Ala83GlyfsTer13 frameshift_variant 3/25 ENST00000252826.10 NP_060106.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TRPM4ENST00000252826.10 linkuse as main transcriptc.247dup p.Ala83GlyfsTer13 frameshift_variant 3/251 NM_017636.4 ENSP00000252826 P1Q8TD43-1

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152150
Hom.:
0
Cov.:
31
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsNov 18, 2021- -
Progressive familial heart block type IB Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 14, 2023This 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 submitterclinical testingAmbry GeneticsMar 24, 2023The 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

Name
Calibrated prediction
Score
Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs754625848; hg19: chr19-49669447; API