15-31002140-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001252024.2(TRPM1):c.4560T>A(p.His1520Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0604 in 1,614,162 control chromosomes in the GnomAD database, including 3,524 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. H1520H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.065 ( 372 hom., cov: 32)

Exomes 𝑓: 0.060 ( 3152 hom. )

Consequence

TRPM1
NM_001252024.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -4.60

Publications

16 publications found

Variant links:

Genes affected

TRPM1 (HGNC:7146): (transient receptor potential cation channel subfamily M member 1) This gene encodes a member of the transient receptor potential melastatin subfamily of transient receptor potential ion channels. The encoded protein is a calcium permeable cation channel that is expressed in melanocytes and may play a role in melanin synthesis. Specific mutations in this gene are the cause autosomal recessive complete congenital stationary night blindness-1C. The expression of this protein is inversely correlated with melanoma aggressiveness and as such it is used as a prognostic marker for melanoma metastasis. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2011]

TRPM1 Gene-Disease associations (from GenCC):

congenital stationary night blindness 1C
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
TRPM1-related retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
congenital stationary night blindness
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TRPM1 links:

ENSG00000259720 (HGNC:58477):

ENSG00000259720 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013849735).

BP6

Variant 15-31002140-A-T is Benign according to our data. Variant chr15-31002140-A-T is described in ClinVar as Benign. ClinVar VariationId is 315490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TRPM1	NM_001252024.2 link	c.4560T>A	p.His1520Gln	missense_variant	Exon 28 of 28	ENST00000256552.11	NP_001238953.1
TRPM1	NM_001252020.2 link	c.4611T>A	p.His1537Gln	missense_variant	Exon 27 of 27		NP_001238949.1
TRPM1	NM_002420.6 link	c.4494T>A	p.His1498Gln	missense_variant	Exon 27 of 27		NP_002411.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM1	ENST00000256552.11 link	c.4560T>A	p.His1520Gln	missense_variant	Exon 28 of 28	1	NM_001252024.2	ENSP00000256552.7

Frequencies

GnomAD3 genomes

AF:

0.0645

AC:

9808

AN:

152166

Hom.:

368

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0751

Gnomad AMI

AF:

0.131

Gnomad AMR

AF:

0.0460

Gnomad ASJ

AF:

0.0620

Gnomad EAS

AF:

0.0160

Gnomad SAS

AF:

0.123

Gnomad FIN

AF:

0.0770

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.0586

Gnomad OTH

AF:

0.0679

GnomAD2 exomes

AF:

0.0632

AC:

15777

AN:

249572

AF XY:

0.0679

show subpopulations

Gnomad AFR exome

AF:

0.0809

Gnomad AMR exome

AF:

0.0336

Gnomad ASJ exome

AF:

0.0696

Gnomad EAS exome

AF:

0.00912

Gnomad FIN exome

AF:

0.0692

Gnomad NFE exome

AF:

0.0582

Gnomad OTH exome

AF:

0.0650

GnomAD4 exome

AF:

0.0599

AC:

87629

AN:

1461878

Hom.:

3152

Cov.:

AF XY:

0.0625

AC XY:

45460

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0771

AC:

2580

AN:

33480

American (AMR)

AF:

0.0354

AC:

1584

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0714

AC:

1865

AN:

26136

East Asian (EAS)

AF:

0.0219

AC:

871

AN:

39700

South Asian (SAS)

AF:

0.131

AC:

11266

AN:

86258

European-Finnish (FIN)

AF:

0.0660

AC:

3524

AN:

53406

Middle Eastern (MID)

AF:

0.105

AC:

603

AN:

5768

European-Non Finnish (NFE)

AF:

0.0554

AC:

61601

AN:

1112010

Other (OTH)

AF:

0.0618

AC:

3735

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

5901

11802

17704

23605

29506

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2302

4604

6906

9208

11510

<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:

0.0645

AC:

9829

AN:

152284

Hom.:

372

Cov.:

AF XY:

0.0661

AC XY:

4921

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0754

AC:

3134

AN:

41538

American (AMR)

AF:

0.0459

AC:

702

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0620

AC:

215

AN:

3468

East Asian (EAS)

AF:

0.0160

AC:

AN:

5186

South Asian (SAS)

AF:

0.124

AC:

601

AN:

4832

European-Finnish (FIN)

AF:

0.0770

AC:

817

AN:

10614

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0585

AC:

3982

AN:

68028

Other (OTH)

AF:

0.0672

AC:

142

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

485

970

1455

1940

2425

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<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:

0.0575

Hom.:

228

Bravo

AF:

0.0603

TwinsUK

AF:

0.0553

AC:

205

ALSPAC

AF:

0.0545

AC:

210

ESP6500AA

AF:

0.0755

AC:

309

ESP6500EA

AF:

0.0560

AC:

469

ExAC

AF:

0.0652

AC:

7891

Asia WGS

AF:

0.0680

AC:

235

AN:

3478

EpiCase

AF:

0.0591

EpiControl

AF:

0.0557

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 05, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Congenital stationary night blindness 1C

Benign:2

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.0010

(source)

DANN

Benign

0.59

DEOGEN2

Benign

0.066

T;.;.;T

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.4

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.29

T;T;T;T

MetaRNN

Benign

0.0014

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;.;.

PhyloP100

-4.6

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.24

N;N;N;.

REVEL

Benign

0.024

Sift

Benign

0.36

T;T;T;.

Sift4G

Benign

0.61

T;T;T;T

Polyphen

0.0

B;.;.;.

Vest4

0.017

MutPred

0.16

Gain of helix (P = 0.0199);.;.;.;

MPC

0.21

ClinPred

0.018

GERP RS

-10

Varity_R

0.041

gMVP

0.11

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over