11-2415234-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_014555.4(TRPM5):c.1366G>A(p.Ala456Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.03 in 1,572,974 control chromosomes in the GnomAD database, including 875 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.023 ( 70 hom., cov: 34)

Exomes 𝑓: 0.031 ( 805 hom. )

Consequence

TRPM5
NM_014555.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.42

Publications

10 publications found

Variant links:

Genes affected

TRPM5 (HGNC:14323): (transient receptor potential cation channel subfamily M member 5) This gene encodes a member of the transient receptor potential (TRP) protein family, which is a diverse group of proteins with structural features typical of ion channels. This protein plays an important role in taste transduction, and has characteristics of a calcium-activated, non-selective cation channel that carries Na+, K+, and Cs+ ions equally well, but not Ca(2+) ions. It is activated by lower concentrations of intracellular Ca(2+), and inhibited by higher concentrations. It is also a highly temperature-sensitive, heat activated channel showing a steep increase of inward currents at temperatures between 15 and 35 degrees Celsius. This gene is located within the Beckwith-Wiedemann syndrome critical region-1 on chromosome 11p15.5, and has been shown to be imprinted, with exclusive expression from the paternal allele. [provided by RefSeq, Oct 2010]

TRPM5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002408743).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0228 (3478/152324) while in subpopulation NFE AF = 0.0351 (2386/68002). AF 95% confidence interval is 0.0339. There are 70 homozygotes in GnomAd4. There are 1624 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 70 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM5	NM_014555.4 link	c.1366G>A	p.Ala456Thr	missense_variant	Exon 14 of 29	ENST00000696290.1	NP_055370.1	Q9NZQ8-1
TRPM5	XM_017017628.2 link	c.1420G>A	p.Ala474Thr	missense_variant	Exon 11 of 26		XP_016873117.1
TRPM5	XM_047426858.1 link	c.1420G>A	p.Ala474Thr	missense_variant	Exon 11 of 26		XP_047282814.1
TRPM5	XM_047426859.1 link	c.217G>A	p.Ala73Thr	missense_variant	Exon 2 of 17		XP_047282815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TRPM5	ENST00000696290.1 link	c.1366G>A	p.Ala456Thr	missense_variant	Exon 14 of 29		NM_014555.4	ENSP00000512529.1	Q9NZQ8-1
TRPM5	ENST00000533060.5 link	c.1366G>A	p.Ala456Thr	missense_variant	Exon 9 of 24	1		ENSP00000434121.1	E9PRW0
TRPM5	ENST00000528453.1 link	c.1366G>A	p.Ala456Thr	missense_variant	Exon 9 of 24	1		ENSP00000436809.1	E9PQF7
TRPM5	ENST00000533881.5 link	c.1348G>A	p.Ala450Thr	missense_variant	Exon 9 of 24	1		ENSP00000434383.1	A0A0C4DGF4

Frequencies

GnomAD3 genomes

AF:

0.0229

AC:

3480

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00630

Gnomad AMI

AF:

0.0231

Gnomad AMR

AF:

0.0217

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.0361

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0351

Gnomad OTH

AF:

0.0306

GnomAD2 exomes

AF:

0.0234

AC:

4137

AN:

176620

AF XY:

0.0238

show subpopulations

Gnomad AFR exome

AF:

0.00543

Gnomad AMR exome

AF:

0.0192

Gnomad ASJ exome

AF:

0.00473

Gnomad EAS exome

AF:

0.0000732

Gnomad FIN exome

AF:

0.0383

Gnomad NFE exome

AF:

0.0380

Gnomad OTH exome

AF:

0.0290

GnomAD4 exome

AF:

0.0308

AC:

43688

AN:

1420650

Hom.:

805

Cov.:

AF XY:

0.0301

AC XY:

21183

AN XY:

704148

show subpopulations

African (AFR)

AF:

0.00522

AC:

171

AN:

32730

American (AMR)

AF:

0.0202

AC:

805

AN:

39904

Ashkenazi Jewish (ASJ)

AF:

0.00518

AC:

132

AN:

25460

East Asian (EAS)

AF:

0.0000530

AC:

AN:

37730

South Asian (SAS)

AF:

0.00354

AC:

291

AN:

82102

European-Finnish (FIN)

AF:

0.0364

AC:

1585

AN:

43584

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.0357

AC:

39109

AN:

1094546

Other (OTH)

AF:

0.0257

AC:

1516

AN:

58928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

2940

5879

8819

11758

14698

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1406

2812

4218

5624

7030

<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:

0.0228

AC:

3478

AN:

152324

Hom.:

Cov.:

AF XY:

0.0218

AC XY:

1624

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00628

AC:

261

AN:

41582

American (AMR)

AF:

0.0216

AC:

331

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00248

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0361

AC:

384

AN:

10628

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0351

AC:

2386

AN:

68002

Other (OTH)

AF:

0.0298

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

182

364

545

727

909

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0282

Hom.:

Bravo

AF:

0.0215

TwinsUK

AF:

0.0326

AC:

121

ALSPAC

AF:

0.0311

AC:

120

ESP6500AA

AF:

0.00820

AC:

ESP6500EA

AF:

0.0324

AC:

273

ExAC

AF:

0.0200

AC:

2346

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.0050

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.092

.;T;.;.

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.23

T;T;T;T

MetaRNN

Benign

0.0024

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

.;L;.;.

PhyloP100

-2.4

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.37

N;N;N;N

REVEL

Benign

0.031

Sift

Benign

0.57

T;T;T;T

Sift4G

Benign

0.54

T;T;T;T

Polyphen

0.0080, 0.0050

.;B;B;.

Vest4

0.030, 0.021, 0.033

MPC

0.086

ClinPred

0.0031

GERP RS

-6.4

Varity_R

0.034

gMVP

0.15

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over