rs144781529

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BP6BS2

The NM_017636.4(TRPM4):c.308A>G(p.Tyr103Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,613,650 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00040 ( 11 hom. )

Consequence

TRPM4
NM_017636.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 2.76

Publications

11 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 -4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.752

BP6

Variant 19-49167957-A-G is Benign according to our data. Variant chr19-49167957-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 222851.

BS2

High AC in GnomAd4 at 58 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.308A>G	p.Tyr103Cys	missense	Exon 4 of 25	NP_060106.2
TRPM4	NM_001195227.2		c.308A>G	p.Tyr103Cys	missense	Exon 4 of 24	NP_001182156.1	Q8TD43-3
TRPM4	NM_001321281.2		c.268-596A>G		intron	N/A	NP_001308210.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRPM4	ENST00000252826.10	TSL:1 MANE Select	c.308A>G	p.Tyr103Cys	missense	Exon 4 of 25	ENSP00000252826.4	Q8TD43-1
TRPM4	ENST00000427978.6	TSL:1	c.308A>G	p.Tyr103Cys	missense	Exon 4 of 24	ENSP00000407492.1	Q8TD43-3
TRPM4	ENST00000595519.5	TSL:1	n.93-303A>G		intron	N/A	ENSP00000469893.1	M0QYK7

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000314

AC:

AN:

251322

AF XY:

0.000331

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.000634

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000403

AC:

589

AN:

1461534

Hom.:

Cov.:

AF XY:

0.000393

AC XY:

286

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000206

AC:

AN:

53298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000502

AC:

558

AN:

1111786

Other (OTH)

AF:

0.000282

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

121

161

201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000381

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000750

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.000586

Hom.:

Bravo

AF:

0.000336

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000321

AC:

EpiCase

AF:

0.000545

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 specified (3)

not provided (2)

Progressive familial heart block type IB (2)

Brugada syndrome (1)

Cardiovascular phenotype (1)

TRPM4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.037

MetaRNN

Pathogenic

0.75

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

2.9

PhyloP100

2.8

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.5

REVEL

Uncertain

0.32

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.89

MVP

0.76

MPC

1.1

ClinPred

0.65

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.70

gMVP

0.77

Mutation Taster

=77/23

polymorphism

(source)

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

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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