rs3784589

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PVS1_StrongBP6_Very_StrongBA1

The NM_001252024.2(TRPM1):c.4189G>T(p.Glu1397*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0604 in 1,614,030 control chromosomes in the GnomAD database, including 3,520 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E1397E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.065 ( 368 hom., cov: 32)

Exomes 𝑓: 0.060 ( 3152 hom. )

Consequence

TRPM1
NM_001252024.2 stop_gained

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.20

Publications

31 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 -12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.141 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

BP6

Variant 15-31002511-C-A is Benign according to our data. Variant chr15-31002511-C-A is described in ClinVar as [Benign]. Clinvar id is 315498.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	UniProt
TRPM1	NM_001252024.2 link	c.4189G>T	p.Glu1397*	stop_gained	Exon 28 of 28	ENST00000256552.11	NP_001238953.1	Q7Z4N2-6
TRPM1	NM_001252020.2 link	c.4240G>T	p.Glu1414*	stop_gained	Exon 27 of 27		NP_001238949.1	Q7Z4N2-5
TRPM1	NM_002420.6 link	c.4123G>T	p.Glu1375*	stop_gained	Exon 27 of 27		NP_002411.3	Q7Z4N2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM1	ENST00000256552.11 link	c.4189G>T	p.Glu1397*	stop_gained	Exon 28 of 28	1	NM_001252024.2	ENSP00000256552.7		Q7Z4N2-6

Frequencies

GnomAD3 genomes

AF:

0.0644

AC:

9799

AN:

152068

Hom.:

364

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0752

Gnomad AMI

AF:

0.132

Gnomad AMR

AF:

0.0462

Gnomad ASJ

AF:

0.0620

Gnomad EAS

AF:

0.0158

Gnomad SAS

AF:

0.124

Gnomad FIN

AF:

0.0768

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.0585

Gnomad OTH

AF:

0.0679

GnomAD2 exomes

AF:

0.0632

AC:

15773

AN:

249512

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:

0.0693

Gnomad NFE exome

AF:

0.0582

Gnomad OTH exome

AF:

0.0650

GnomAD4 exome

AF:

0.0599

AC:

87603

AN:

1461846

Hom.:

3152

Cov.:

AF XY:

0.0625

AC XY:

45449

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.0770

AC:

2577

AN:

33480

American (AMR)

AF:

0.0354

AC:

1584

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0714

AC:

1865

AN:

26134

East Asian (EAS)

AF:

0.0219

AC:

871

AN:

39700

South Asian (SAS)

AF:

0.131

AC:

11262

AN:

86256

European-Finnish (FIN)

AF:

0.0660

AC:

3525

AN:

53390

Middle Eastern (MID)

AF:

0.105

AC:

603

AN:

5768

European-Non Finnish (NFE)

AF:

0.0554

AC:

61584

AN:

1112000

Other (OTH)

AF:

0.0618

AC:

3732

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

5461

10923

16384

21846

27307

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:

9820

AN:

152184

Hom.:

368

Cov.:

AF XY:

0.0660

AC XY:

4911

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.0755

AC:

3134

AN:

41510

American (AMR)

AF:

0.0460

AC:

704

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0620

AC:

215

AN:

3466

East Asian (EAS)

AF:

0.0159

AC:

AN:

5172

South Asian (SAS)

AF:

0.125

AC:

601

AN:

4826

European-Finnish (FIN)

AF:

0.0768

AC:

813

AN:

10590

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0585

AC:

3975

AN:

68006

Other (OTH)

AF:

0.0672

AC:

142

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

472

944

1415

1887

2359

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:

0.0576

Hom.:

1089

Bravo

AF:

0.0603

TwinsUK

AF:

0.0550

AC:

204

ALSPAC

AF:

0.0547

AC:

211

ESP6500AA

AF:

0.0793

AC:

293

ESP6500EA

AF:

0.0565

AC:

463

ExAC

AF:

0.0653

AC:

7888

Asia WGS

AF:

0.0680

AC:

235

AN:

3478

EpiCase

AF:

0.0590

EpiControl

AF:

0.0557

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital stationary night blindness 1C

Benign:2

Mar 06, 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. -

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.90

PhyloP100

2.2

Vest4

0.58

GERP RS

5.0

Mutation Taster

=177/23

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