rs78444754

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_017636.4(TRPM4):c.449-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0246 in 1,614,016 control chromosomes in the GnomAD database, including 574 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 25 hom., cov: 30)

Exomes 𝑓: 0.025 ( 549 hom. )

Consequence

TRPM4
NM_017636.4 intron

Scores

Splicing: ADA: 0.001161

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.410

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]

TRPM4 links:

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=-0.83).

BP6

Variant 19-49168250-G-A is Benign according to our data. Variant chr19-49168250-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49168250-G-A is described in Lovd as [Benign]. Variant chr19-49168250-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0181 (2761/152292) while in subpopulation SAS AF= 0.0363 (175/4824). AF 95% confidence interval is 0.0319. There are 25 homozygotes in gnomad4. There are 1327 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2761 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM4	NM_017636.4 link	c.449-10G>A		intron_variant	Intron 4 of 24	ENST00000252826.10	NP_060106.2	Q8TD43-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM4	ENST00000252826.10 link	c.449-10G>A		intron_variant	Intron 4 of 24	1	NM_017636.4	ENSP00000252826.4		Q8TD43-1

Frequencies

GnomAD3 genomes

AF:

0.0181

AC:

2758

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00514

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0118

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0358

Gnomad FIN

AF:

0.0279

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0268

Gnomad OTH

AF:

0.0134

GnomAD3 exomes

AF:

0.0201

AC:

5059

AN:

251324

Hom.:

AF XY:

0.0210

AC XY:

2856

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.00357

Gnomad AMR exome

AF:

0.00905

Gnomad ASJ exome

AF:

0.0129

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0339

Gnomad FIN exome

AF:

0.0287

Gnomad NFE exome

AF:

0.0246

Gnomad OTH exome

AF:

0.0168

GnomAD4 exome

AF:

0.0253

AC:

36922

AN:

1461724

Hom.:

549

Cov.:

AF XY:

0.0254

AC XY:

18439

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.00379

Gnomad4 AMR exome

AF:

0.00919

Gnomad4 ASJ exome

AF:

0.0135

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0336

Gnomad4 FIN exome

AF:

0.0288

Gnomad4 NFE exome

AF:

0.0273

Gnomad4 OTH exome

AF:

0.0208

GnomAD4 genome

AF:

0.0181

AC:

2761

AN:

152292

Hom.:

Cov.:

AF XY:

0.0178

AC XY:

1327

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00513

Gnomad4 AMR

AF:

0.0118

Gnomad4 ASJ

AF:

0.00979

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0363

Gnomad4 FIN

AF:

0.0279

Gnomad4 NFE

AF:

0.0268

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.0205

Hom.:

Bravo

AF:

0.0155

Asia WGS

AF:

0.0210

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 09, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 04, 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. -

not provided

Benign:2

Nov 01, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Progressive familial heart block type IB

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.7

DANN

Benign

0.74

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0012

dbscSNV1_RF

Benign

0.0060

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over