15-31042159-C-T

Position:

chr15-31042159-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001252024.2(TRPM1):c.1879G>A(p.Val627Met) variant causes a missense change. The variant allele was found at a frequency of 0.0304 in 1,614,128 control chromosomes in the GnomAD database, including 860 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V627L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.023 ( 70 hom., cov: 32)

Exomes 𝑓: 0.031 ( 790 hom. )

Consequence

TRPM1
NM_001252024.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.83

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004008323).

BP6

Variant 15-31042159-C-T is Benign according to our data. Variant chr15-31042159-C-T is described in ClinVar as [Benign]. Clinvar id is 315519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-31042159-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0234 (3562/152306) while in subpopulation NFE AF= 0.0367 (2494/68016). AF 95% confidence interval is 0.0355. There are 70 homozygotes in gnomad4. There are 1619 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 70 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TRPM1	NM_001252024.2 linkuse as main transcript	c.1879G>A	p.Val627Met	missense_variant	17/28	ENST00000256552.11
TRPM1	NM_001252020.2 linkuse as main transcript	c.1930G>A	p.Val644Met	missense_variant	16/27
TRPM1	NM_002420.6 linkuse as main transcript	c.1813G>A	p.Val605Met	missense_variant	16/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM1	ENST00000256552.11 linkuse as main transcript	c.1879G>A	p.Val627Met	missense_variant	17/28	1	NM_001252024.2	P4	Q7Z4N2-6

Frequencies

GnomAD3 genomes

AF:

0.0234

AC:

3564

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00642

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.0281

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0116

Gnomad FIN

AF:

0.0118

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0367

Gnomad OTH

AF:

0.0263

GnomAD3 exomes

AF:

0.0242

AC:

6034

AN:

249276

Hom.:

AF XY:

0.0242

AC XY:

3270

AN XY:

135260

show subpopulations

Gnomad AFR exome

AF:

0.00549

Gnomad AMR exome

AF:

0.0187

Gnomad ASJ exome

AF:

0.0186

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0128

Gnomad FIN exome

AF:

0.0155

Gnomad NFE exome

AF:

0.0374

Gnomad OTH exome

AF:

0.0277

GnomAD4 exome

AF:

0.0311

AC:

45509

AN:

1461822

Hom.:

790

Cov.:

AF XY:

0.0306

AC XY:

22261

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00594

Gnomad4 AMR exome

AF:

0.0195

Gnomad4 ASJ exome

AF:

0.0215

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0139

Gnomad4 FIN exome

AF:

0.0165

Gnomad4 NFE exome

AF:

0.0360

Gnomad4 OTH exome

AF:

0.0271

GnomAD4 genome

AF:

0.0234

AC:

3562

AN:

152306

Hom.:

Cov.:

AF XY:

0.0217

AC XY:

1619

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00640

Gnomad4 AMR

AF:

0.0281

Gnomad4 ASJ

AF:

0.0225

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0114

Gnomad4 FIN

AF:

0.0118

Gnomad4 NFE

AF:

0.0367

Gnomad4 OTH

AF:

0.0260

Alfa

AF:

0.0334

Hom.:

220

Bravo

AF:

0.0232

TwinsUK

AF:

0.0334

AC:

124

ALSPAC

AF:

0.0361

AC:

139

ESP6500AA

AF:

0.00626

AC:

ESP6500EA

AF:

0.0378

AC:

323

ExAC

AF:

0.0248

AC:

3010

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

Congenital stationary night blindness 1C

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

0.12

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.079

T;.;.;T;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.78

T;T;T;T;T

MetaRNN

Benign

0.0040

T;T;T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.6

L;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.62

N;N;N;.;N

REVEL

Benign

0.19

Sift

Benign

0.24

T;T;T;.;T

Sift4G

Benign

0.22

T;T;T;T;T

Polyphen

0.99

D;.;.;.;.

Vest4

0.26

MPC

0.24

ClinPred

0.031

GERP RS

3.8

Varity_R

0.13

gMVP

0.41

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over