rs144647383

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_017636.4(TRPM4):ā€‹c.3405A>Cā€‹(p.Ala1135=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000779 in 1,613,956 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0042 ( 8 hom., cov: 31)
Exomes š‘“: 0.00042 ( 8 hom. )

Consequence

TRPM4
NM_017636.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -3.86
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 Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.89).
BP6
Variant 19-49210786-A-C is Benign according to our data. Variant chr19-49210786-A-C is described in ClinVar as [Benign]. Clinvar id is 241178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49210786-A-C is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-3.86 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0042 (640/152290) while in subpopulation AFR AF= 0.0147 (612/41572). AF 95% confidence interval is 0.0138. There are 8 homozygotes in gnomad4. There are 300 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 640 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TRPM4NM_017636.4 linkuse as main transcriptc.3405A>C p.Ala1135= synonymous_variant 22/25 ENST00000252826.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TRPM4ENST00000252826.10 linkuse as main transcriptc.3405A>C p.Ala1135= synonymous_variant 22/251 NM_017636.4 P1Q8TD43-1

Frequencies

GnomAD3 genomes
AF:
0.00421
AC:
640
AN:
152172
Hom.:
8
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0148
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00157
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00192
GnomAD3 exomes
AF:
0.00108
AC:
270
AN:
249632
Hom.:
7
AF XY:
0.000711
AC XY:
96
AN XY:
134980
show subpopulations
Gnomad AFR exome
AF:
0.0156
Gnomad AMR exome
AF:
0.000493
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000328
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000888
Gnomad OTH exome
AF:
0.000330
GnomAD4 exome
AF:
0.000422
AC:
617
AN:
1461666
Hom.:
8
Cov.:
34
AF XY:
0.000337
AC XY:
245
AN XY:
727098
show subpopulations
Gnomad4 AFR exome
AF:
0.0159
Gnomad4 AMR exome
AF:
0.000514
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.000811
GnomAD4 genome
AF:
0.00420
AC:
640
AN:
152290
Hom.:
8
Cov.:
31
AF XY:
0.00403
AC XY:
300
AN XY:
74458
show subpopulations
Gnomad4 AFR
AF:
0.0147
Gnomad4 AMR
AF:
0.00157
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00190
Alfa
AF:
0.00249
Hom.:
0
Bravo
AF:
0.00503
Asia WGS
AF:
0.00144
AC:
5
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 09, 2024Variant summary: TRPM4 c.3405A>C results in a synonymous change. Several computational tools predict a significant impact on normal splicing: One predict the variant strengthens a cryptic 3' acceptor site. Two predict the variant creates the cryptic 3' acceptor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0011 in 249632 control chromosomes in the gnomAD database, including 7 homozygotes. The observed variant frequency is approximately 432 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. To our knowledge, no occurrence of c.3405A>C in individuals affected with Progressive Familial Heart Block Type 1B and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 241178). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitterclinical testingGeneDxFeb 13, 2017This 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. -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesDec 27, 2019- -
Progressive familial heart block type IB Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 28, 2024- -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJan 15, 2016This alteration is classified as 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_noAF
Benign
-0.89
CADD
Benign
0.50
DANN
Benign
0.55

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: rs144647383; hg19: chr19-49714043; API