Genetic Variant TRPM4:p.Val1025Phe (chr19-49202083-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_017636.4(TRPM4):c.3073G>T(p.Val1025Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1025I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

TRPM4
NM_017636.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.916

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

erythrokeratodermia variabilis et progressiva 6
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
progressive familial heart block type IB
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
erythrokeratodermia variabilis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
progressive familial heart block
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Brugada syndrome
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen

TRPM4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29650205).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017636.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRPM4	NM_017636.4	MANE Select	c.3073G>T	p.Val1025Phe	missense	Exon 20 of 25	NP_060106.2
TRPM4	NM_001321281.2		c.2728G>T	p.Val910Phe	missense	Exon 18 of 23	NP_001308210.1
TRPM4	NM_001195227.2		c.2638G>T	p.Val880Phe	missense	Exon 19 of 24	NP_001182156.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRPM4	ENST00000252826.10	TSL:1 MANE Select	c.3073G>T	p.Val1025Phe	missense	Exon 20 of 25	ENSP00000252826.4
TRPM4	ENST00000427978.6	TSL:1	c.2638G>T	p.Val880Phe	missense	Exon 19 of 24	ENSP00000407492.1
TRPM4	ENST00000595519.5	TSL:1	n.*2483G>T		non_coding_transcript_exon	Exon 18 of 23	ENSP00000469893.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251390

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.26

CADD

Benign

3.8

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.82

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.058

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.058

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.5

PhyloP100

-0.92

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.46

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0020

Polyphen

0.95

Vest4

0.30

MVP

0.61

MPC

1.1

ClinPred

0.94

GERP RS

-6.3

Varity_R

0.44

gMVP

0.82

Mutation Taster

=73/27

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over