Genetic Variant TRPM4:p.Phe414Leu (chr19-49181440-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000252826.10(TRPM4):c.1242T>A(p.Phe414Leu) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F414F) has been classified as Benign.

Frequency

Genomes: not found (cov: 30)

Consequence

TRPM4
ENST00000252826.10 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.45

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.755

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000252826.10. 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.1242T>A	p.Phe414Leu	missense	Exon 10 of 25	NP_060106.2
TRPM4	NM_001321281.2		c.897T>A	p.Phe299Leu	missense	Exon 8 of 23	NP_001308210.1
TRPM4	NM_001195227.2		c.1242T>A	p.Phe414Leu	missense	Exon 10 of 24	NP_001182156.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRPM4	ENST00000252826.10	TSL:1 MANE Select	c.1242T>A	p.Phe414Leu	missense	Exon 10 of 25	ENSP00000252826.4
TRPM4	ENST00000427978.6	TSL:1	c.1242T>A	p.Phe414Leu	missense	Exon 10 of 24	ENSP00000407492.1
TRPM4	ENST00000595519.5	TSL:1	n.*652T>A		non_coding_transcript_exon	Exon 8 of 23	ENSP00000469893.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

Eigen

Benign

0.092

Eigen_PC

Benign

0.074

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.036

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.9

PhyloP100

2.5

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.5

REVEL

Benign

0.21

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.97

Vest4

0.78

MutPred

0.50

Gain of helix (P = 0.2294)

MVP

0.88

MPC

0.98

ClinPred

0.99

GERP RS

2.8

Varity_R

0.97

gMVP

0.80

Mutation Taster

=39/61

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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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