19-49157855-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017636.4(TRPM4):​c.-12G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,534,342 control chromosomes in the GnomAD database, including 58,096 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 4098 hom., cov: 31)
Exomes 𝑓: 0.27 ( 53998 hom. )

Consequence

TRPM4
NM_017636.4 5_prime_UTR

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.08
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 19-49157855-G-A is Benign according to our data. Variant chr19-49157855-G-A is described in ClinVar as [Benign]. Clinvar id is 260834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49157855-G-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TRPM4NM_017636.4 linkc.-12G>A 5_prime_UTR_variant Exon 1 of 25 ENST00000252826.10 NP_060106.2 Q8TD43-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TRPM4ENST00000252826 linkc.-12G>A 5_prime_UTR_variant Exon 1 of 25 1 NM_017636.4 ENSP00000252826.4 Q8TD43-1

Frequencies

GnomAD3 genomes
AF:
0.208
AC:
31620
AN:
151994
Hom.:
4098
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0680
Gnomad AMI
AF:
0.242
Gnomad AMR
AF:
0.177
Gnomad ASJ
AF:
0.277
Gnomad EAS
AF:
0.0523
Gnomad SAS
AF:
0.307
Gnomad FIN
AF:
0.264
Gnomad MID
AF:
0.297
Gnomad NFE
AF:
0.291
Gnomad OTH
AF:
0.233
GnomAD3 exomes
AF:
0.237
AC:
32070
AN:
135490
Hom.:
4360
AF XY:
0.247
AC XY:
17942
AN XY:
72678
show subpopulations
Gnomad AFR exome
AF:
0.0661
Gnomad AMR exome
AF:
0.154
Gnomad ASJ exome
AF:
0.288
Gnomad EAS exome
AF:
0.0587
Gnomad SAS exome
AF:
0.306
Gnomad FIN exome
AF:
0.269
Gnomad NFE exome
AF:
0.292
Gnomad OTH exome
AF:
0.261
GnomAD4 exome
AF:
0.273
AC:
376879
AN:
1382230
Hom.:
53998
Cov.:
35
AF XY:
0.275
AC XY:
187854
AN XY:
682050
show subpopulations
Gnomad4 AFR exome
AF:
0.0584
Gnomad4 AMR exome
AF:
0.159
Gnomad4 ASJ exome
AF:
0.291
Gnomad4 EAS exome
AF:
0.0484
Gnomad4 SAS exome
AF:
0.316
Gnomad4 FIN exome
AF:
0.275
Gnomad4 NFE exome
AF:
0.287
Gnomad4 OTH exome
AF:
0.256
GnomAD4 genome
AF:
0.208
AC:
31609
AN:
152112
Hom.:
4098
Cov.:
31
AF XY:
0.208
AC XY:
15460
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.0679
Gnomad4 AMR
AF:
0.176
Gnomad4 ASJ
AF:
0.277
Gnomad4 EAS
AF:
0.0519
Gnomad4 SAS
AF:
0.308
Gnomad4 FIN
AF:
0.264
Gnomad4 NFE
AF:
0.291
Gnomad4 OTH
AF:
0.230
Alfa
AF:
0.170
Hom.:
536
Bravo
AF:
0.192
Asia WGS
AF:
0.163
AC:
569
AN:
3476

ClinVar

Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6
-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 04, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 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. -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 22, 2016
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Progressive familial heart block type IB Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
CADD
Benign
7.3
DANN
Benign
0.95
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.0

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

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

Other links and lift over

dbSNP: rs3760663; hg19: chr19-49661112; API