rs113984787

Positions:

chr19-49167950-G-A

Variant summary

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

The ENST00000252826.10(TRPM4):c.301G>A(p.Ala101Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,566,778 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0066 ( 14 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 37 hom. )

Consequence

TRPM4
ENST00000252826.10 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.266

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 (MetaRNN=0.0020435154).

BP6

Variant 19-49167950-G-A is Benign according to our data. Variant chr19-49167950-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 220959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49167950-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00663 (987/148828) while in subpopulation SAS AF= 0.0109 (50/4584). AF 95% confidence interval is 0.0085. There are 14 homozygotes in gnomad4. There are 497 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 987 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM4	NM_017636.4 linkuse as main transcript	c.301G>A	p.Ala101Thr	missense_variant	4/25	ENST00000252826.10	NP_060106.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM4	ENST00000252826.10 linkuse as main transcript	c.301G>A	p.Ala101Thr	missense_variant	4/25	1	NM_017636.4	ENSP00000252826	P1	Q8TD43-1

Frequencies

GnomAD3 genomes

AF:

0.00663

AC:

986

AN:

148716

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00564

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00258

Gnomad ASJ

AF:

0.0123

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0109

Gnomad FIN

AF:

0.0115

Gnomad MID

AF:

0.00980

Gnomad NFE

AF:

0.00754

Gnomad OTH

AF:

0.00340

GnomAD3 exomes

AF:

0.0000828

AC:

AN:

241570

Hom.:

AF XY:

0.0000844

AC XY:

AN XY:

130256

show subpopulations

Gnomad AFR exome

AF:

0.000443

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000210

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000348

Gnomad NFE exome

AF:

0.0000275

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.00163

AC:

2312

AN:

1417950

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

1316

AN XY:

704416

show subpopulations

Gnomad4 AFR exome

AF:

0.00223

Gnomad4 AMR exome

AF:

0.000972

Gnomad4 ASJ exome

AF:

0.00507

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00432

Gnomad4 FIN exome

AF:

0.00526

Gnomad4 NFE exome

AF:

0.00124

Gnomad4 OTH exome

AF:

0.00174

GnomAD4 genome

AF:

0.00663

AC:

987

AN:

148828

Hom.:

Cov.:

AF XY:

0.00684

AC XY:

497

AN XY:

72662

show subpopulations

Gnomad4 AFR

AF:

0.00564

Gnomad4 AMR

AF:

0.00257

Gnomad4 ASJ

AF:

0.0123

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0109

Gnomad4 FIN

AF:

0.0115

Gnomad4 NFE

AF:

0.00755

Gnomad4 OTH

AF:

0.00337

Alfa

AF:

0.0172

Hom.:

Bravo

AF:

0.0145

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.0140

AC:

ESP6500AA

AF:

0.0154

AC:

ESP6500EA

AF:

0.0187

AC:

161

ExAC

AF:

0.0211

AC:

2565

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 19, 2023	Variant summary: TRPM4 c.301G>A (p.Ala101Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-05 in 241570 control chromosomes. The observed variant frequency is approximately 33 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.301G>A in individuals affected with Progressive Familial Heart Block Type 1B and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	TRPM4: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Progressive familial heart block type IB

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

TRPM4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 02, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2015

This 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

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.85

CADD

Benign

9.3

DANN

Benign

0.95

DEOGEN2

Benign

0.10

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0092

LIST_S2

Benign

0.13

T;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.67

N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

0.70

N;N

REVEL

Benign

0.030

Sift

Benign

0.36

T;T

Sift4G

Benign

0.70

T;T

Polyphen

0.0

B;B

Vest4

0.052

MPC

0.28

ClinPred

0.014

GERP RS

2.3

Varity_R

0.047

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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