15-31002140-A-T

Position:

chr15-31002140-A-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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

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=0.0013849735).

BP6

Variant 15-31002140-A-T is Benign according to our data. Variant chr15-31002140-A-T is described in ClinVar as [Benign]. Clinvar id 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/exons	MANE	Protein
TRPM1	NM_001252024.2 linkuse as main transcript	c.4560T>A	p.His1520Gln	missense_variant	28/28	ENST00000256552.11	NP_001238953.1
TRPM1	NM_001252020.2 linkuse as main transcript	c.4611T>A	p.His1537Gln	missense_variant	27/27		NP_001238949.1
TRPM1	NM_002420.6 linkuse as main transcript	c.4494T>A	p.His1498Gln	missense_variant	27/27		NP_002411.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM1	ENST00000256552.11 linkuse as main transcript	c.4560T>A	p.His1520Gln	missense_variant	28/28	1	NM_001252024.2	ENSP00000256552	P4	Q7Z4N2-6
	ENST00000665655.1 linkuse as main transcript	n.71+9899A>T		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes

AF:

0.0632

AC:

15777

AN:

249572

Hom.:

680

AF XY:

0.0679

AC XY:

9199

AN XY:

135402

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 SAS exome

AF:

0.131

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

Gnomad4 AFR exome

AF:

0.0771

Gnomad4 AMR exome

AF:

0.0354

Gnomad4 ASJ exome

AF:

0.0714

Gnomad4 EAS exome

AF:

0.0219

Gnomad4 SAS exome

AF:

0.131

Gnomad4 FIN exome

AF:

0.0660

Gnomad4 NFE exome

AF:

0.0554

Gnomad4 OTH exome

AF:

0.0618

GnomAD4 genome

AF:

0.0645

AC:

9829

AN:

152284

Hom.:

372

Cov.:

AF XY:

0.0661

AC XY:

4921

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0754

Gnomad4 AMR

AF:

0.0459

Gnomad4 ASJ

AF:

0.0620

Gnomad4 EAS

AF:

0.0160

Gnomad4 SAS

AF:

0.124

Gnomad4 FIN

AF:

0.0770

Gnomad4 NFE

AF:

0.0585

Gnomad4 OTH

AF:

0.0672

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2019	- -
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	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

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

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;.;.;.

MutationTaster

Benign

1.0

N;N;N;N

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

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