NM_017636.4:c.1294G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_017636.4(TRPM4):c.1294G>A(p.Ala432Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000346 in 1,613,876 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00049 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 4 hom. )

Consequence

TRPM4
NM_017636.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6B:5

Conservation

PhyloP100: 5.06

Publications

32 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: Labcorp Genetics (formerly Invitae), G2P, 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 19-49182608-G-A is Benign according to our data. Variant chr19-49182608-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35487.

BS2

High AC in GnomAd4 at 75 AD gene.

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	UniProt
TRPM4	NM_017636.4	MANE Select	c.1294G>A	p.Ala432Thr	missense	Exon 11 of 25	NP_060106.2
TRPM4	NM_001321281.2		c.949G>A	p.Ala317Thr	missense	Exon 9 of 23	NP_001308210.1
TRPM4	NM_001195227.2		c.1294G>A	p.Ala432Thr	missense	Exon 11 of 24	NP_001182156.1	Q8TD43-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRPM4	ENST00000252826.10	TSL:1 MANE Select	c.1294G>A	p.Ala432Thr	missense	Exon 11 of 25	ENSP00000252826.4	Q8TD43-1
TRPM4	ENST00000427978.6	TSL:1	c.1294G>A	p.Ala432Thr	missense	Exon 11 of 24	ENSP00000407492.1	Q8TD43-3
TRPM4	ENST00000595519.5	TSL:1	n.*704G>A		non_coding_transcript_exon	Exon 9 of 23	ENSP00000469893.1	M0QYK7

Frequencies

GnomAD3 genomes

AF:

0.000506

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000471

AC:

118

AN:

250558

AF XY:

0.000494

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000495

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.000330

AC:

483

AN:

1461592

Hom.:

Cov.:

AF XY:

0.000342

AC XY:

249

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33480

American (AMR)

AF:

0.00114

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000191

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000290

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000376

AC:

AN:

53126

Middle Eastern (MID)

AF:

0.0165

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000201

AC:

223

AN:

1112010

Other (OTH)

AF:

0.00114

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

114

142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000493

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41562

American (AMR)

AF:

0.00222

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68020

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000419

Hom.:

Bravo

AF:

0.000672

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000494

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000771

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Progressive familial heart block type IB (4)

Brugada syndrome (1)

Cardiovascular phenotype (1)

not specified (1)

Progressive familial heart block, type 1A (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.44

MetaRNN

Uncertain

0.57

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

PhyloP100

5.1

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.93

MVP

0.97

MPC

0.95

ClinPred

0.22

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.73

gMVP

0.77

Mutation Taster

=2/98

disease causing

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over