15-31076920-A-G

Position:

chr15-31076920-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 10P and 16B. PVS1PS1_ModerateBP6_Very_StrongBA1

The ENST00000397795.7(TRPM1):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.821 in 1,606,726 control chromosomes in the GnomAD database, including 544,125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.85 ( 55463 hom., cov: 32)

Exomes 𝑓: 0.82 ( 488662 hom. )

Consequence

TRPM1
ENST00000397795.7 start_lost

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0460

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in ENST00000397795.7 (TRPM1) was described as [Likely_pathogenic] in ClinVar as 191053

BP6

Variant 15-31076920-A-G is Benign according to our data. Variant chr15-31076920-A-G is described in ClinVar as [Benign]. Clinvar id is 315540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-31076920-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.954 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TRPM1	NM_001252024.2 linkuse as main transcript	c.68T>C	p.Met23Thr	missense_variant	3/28	ENST00000256552.11	NP_001238953.1
TRPM1	NM_002420.6 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	2/27		NP_002411.3
TRPM1	NM_001252030.2 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	2/3		NP_001238959.1
TRPM1	NM_001252020.2 linkuse as main transcript	c.119T>C	p.Met40Thr	missense_variant	2/27		NP_001238949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM1	ENST00000256552.11 linkuse as main transcript	c.68T>C	p.Met23Thr	missense_variant	3/28	1	NM_001252024.2	ENSP00000256552	P4	Q7Z4N2-6

Frequencies

GnomAD3 genomes

AF:

0.852

AC:

129532

AN:

152054

Hom.:

55414

Cov.:

show subpopulations

Gnomad AFR

AF:

0.902

Gnomad AMI

AF:

0.898

Gnomad AMR

AF:

0.874

Gnomad ASJ

AF:

0.854

Gnomad EAS

AF:

0.977

Gnomad SAS

AF:

0.871

Gnomad FIN

AF:

0.811

Gnomad MID

AF:

0.816

Gnomad NFE

AF:

0.811

Gnomad OTH

AF:

0.838

GnomAD3 exomes

AF:

0.848

AC:

211620

AN:

249508

Hom.:

90241

AF XY:

0.843

AC XY:

114156

AN XY:

135378

show subpopulations

Gnomad AFR exome

AF:

0.903

Gnomad AMR exome

AF:

0.912

Gnomad ASJ exome

AF:

0.851

Gnomad EAS exome

AF:

0.984

Gnomad SAS exome

AF:

0.863

Gnomad FIN exome

AF:

0.811

Gnomad NFE exome

AF:

0.803

Gnomad OTH exome

AF:

0.843

GnomAD4 exome

AF:

0.818

AC:

1190110

AN:

1454554

Hom.:

488662

Cov.:

AF XY:

0.819

AC XY:

593133

AN XY:

724094

show subpopulations

Gnomad4 AFR exome

AF:

0.905

Gnomad4 AMR exome

AF:

0.908

Gnomad4 ASJ exome

AF:

0.848

Gnomad4 EAS exome

AF:

0.970

Gnomad4 SAS exome

AF:

0.861

Gnomad4 FIN exome

AF:

0.811

Gnomad4 NFE exome

AF:

0.802

Gnomad4 OTH exome

AF:

0.835

GnomAD4 genome

AF:

0.852

AC:

129637

AN:

152172

Hom.:

55463

Cov.:

AF XY:

0.854

AC XY:

63508

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.902

Gnomad4 AMR

AF:

0.874

Gnomad4 ASJ

AF:

0.854

Gnomad4 EAS

AF:

0.977

Gnomad4 SAS

AF:

0.871

Gnomad4 FIN

AF:

0.811

Gnomad4 NFE

AF:

0.811

Gnomad4 OTH

AF:

0.837

Alfa

AF:

0.818

Hom.:

122623

Bravo

AF:

0.858

TwinsUK

AF:

0.790

AC:

2930

ALSPAC

AF:

0.798

AC:

3074

ESP6500AA

AF:

0.892

AC:

3317

ESP6500EA

AF:

0.801

AC:

6581

ExAC

AF:

0.845

AC:

102011

Asia WGS

AF:

0.912

AC:

3171

AN:

3478

EpiCase

AF:

0.810

EpiControl

AF:

0.805

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Congenital stationary night blindness 1C

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
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

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

6.8

DANN

Benign

0.87

DEOGEN2

Benign

0.064

T;.;.;T;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.014

LIST_S2

Uncertain

0.90

D;T;T;D;D;D

MetaRNN

Benign

8.5e-7

T;T;T;T;T;T

MetaSVM

Benign

-0.94

MutationTaster

Benign

0.0

P;P;P;P

PrimateAI

Benign

0.43

PROVEAN

Benign

1.4

N;N;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.068

T;T;T;D;T;D

Sift4G

Benign

0.088

T;T;T;D;T;D

Polyphen

0.0

B;.;.;.;.;.

Vest4

0.049

MPC

0.24

ClinPred

0.0018

GERP RS

2.4

Varity_R

0.066

gMVP

0.13

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