chr19-49157877-C-G

Position:

chr19-49157877-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_017636.4(TRPM4):c.11C>G(p.Pro4Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000912 in 1,534,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000094 ( 0 hom. )

Consequence

TRPM4
NM_017636.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.276

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07735908).

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM4	NM_017636.4 linkuse as main transcript	c.11C>G	p.Pro4Arg	missense_variant	1/25	ENST00000252826.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM4	ENST00000252826.10 linkuse as main transcript	c.11C>G	p.Pro4Arg	missense_variant	1/25	1	NM_017636.4	P1	Q8TD43-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000146

AC:

AN:

137216

Hom.:

AF XY:

0.00

AC XY:

AN XY:

73354

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000120

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000188

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000940

AC:

AN:

1382666

Hom.:

Cov.:

AF XY:

0.0000103

AC XY:

AN XY:

682280

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000398

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.0000253

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000835

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Progressive familial heart block type IB;C5193144:Erythrokeratodermia variabilis et progressiva 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 21, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 27, 2019

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -

Progressive familial heart block type IB

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 02, 2023

An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. ClinVar contains an entry for this variant (Variation ID: 577534). This variant has not been reported in the literature in individuals affected with TRPM4-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 4 of the TRPM4 protein (p.Pro4Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

T;T;T;.

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.72

T;T;T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.077

T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.1

.;L;.;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.080

.;N;.;N

REVEL

Benign

0.12

Sift

Benign

0.080

.;T;.;T

Sift4G

Uncertain

0.017

D;T;D;T

Polyphen

0.18, 0.18

.;B;.;B

Vest4

0.13, 0.16, 0.14

MutPred

0.32

Gain of MoRF binding (P = 0.0045);Gain of MoRF binding (P = 0.0045);Gain of MoRF binding (P = 0.0045);Gain of MoRF binding (P = 0.0045);

MVP

0.58

MPC

0.37

ClinPred

0.16

GERP RS

0.43

Varity_R

0.084

gMVP

0.18

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.

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