rs17227996

Positions:

chr15-31002948-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001252024.2(TRPM1):c.3752A>C(p.Asn1251Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0519 in 1,601,860 control chromosomes in the GnomAD database, including 2,567 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 0.041 ( 194 hom., cov: 32)

Exomes 𝑓: 0.053 ( 2373 hom. )

Consequence

TRPM1
NM_001252024.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.611

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=0.0012834966).

BP6

Variant 15-31002948-T-G is Benign according to our data. Variant chr15-31002948-T-G is described in ClinVar as [Benign]. Clinvar id is 315501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0595 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TRPM1	NM_001252024.2 linkuse as main transcript	c.3752A>C	p.Asn1251Thr	missense_variant	28/28	ENST00000256552.11
TRPM1	NM_001252020.2 linkuse as main transcript	c.3803A>C	p.Asn1268Thr	missense_variant	27/27
TRPM1	NM_002420.6 linkuse as main transcript	c.3686A>C	p.Asn1229Thr	missense_variant	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM1	ENST00000256552.11 linkuse as main transcript	c.3752A>C	p.Asn1251Thr	missense_variant	28/28	1	NM_001252024.2	P4	Q7Z4N2-6
	ENST00000665655.1 linkuse as main transcript	n.71+10707T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0406

AC:

6180

AN:

152184

Hom.:

194

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0112

Gnomad AMI

AF:

0.0800

Gnomad AMR

AF:

0.0304

Gnomad ASJ

AF:

0.0285

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.0774

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0611

Gnomad OTH

AF:

0.0306

GnomAD3 exomes

AF:

0.0408

AC:

9929

AN:

243126

Hom.:

291

AF XY:

0.0409

AC XY:

5391

AN XY:

131862

show subpopulations

Gnomad AFR exome

AF:

0.0113

Gnomad AMR exome

AF:

0.0225

Gnomad ASJ exome

AF:

0.0303

Gnomad EAS exome

AF:

0.000112

Gnomad SAS exome

AF:

0.00636

Gnomad FIN exome

AF:

0.0789

Gnomad NFE exome

AF:

0.0595

Gnomad OTH exome

AF:

0.0431

GnomAD4 exome

AF:

0.0531

AC:

77003

AN:

1449558

Hom.:

2373

Cov.:

AF XY:

0.0518

AC XY:

37288

AN XY:

719390

show subpopulations

Gnomad4 AFR exome

AF:

0.00943

Gnomad4 AMR exome

AF:

0.0225

Gnomad4 ASJ exome

AF:

0.0316

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00638

Gnomad4 FIN exome

AF:

0.0788

Gnomad4 NFE exome

AF:

0.0610

Gnomad4 OTH exome

AF:

0.0442

GnomAD4 genome

AF:

0.0406

AC:

6180

AN:

152302

Hom.:

194

Cov.:

AF XY:

0.0397

AC XY:

2959

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0112

Gnomad4 AMR

AF:

0.0304

Gnomad4 ASJ

AF:

0.0285

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00642

Gnomad4 FIN

AF:

0.0774

Gnomad4 NFE

AF:

0.0611

Gnomad4 OTH

AF:

0.0302

Alfa

AF:

0.0534

Hom.:

573

Bravo

AF:

0.0364

TwinsUK

AF:

0.0596

AC:

221

ALSPAC

AF:

0.0646

AC:

249

ESP6500AA

AF:

0.0110

AC:

ESP6500EA

AF:

0.0607

AC:

503

ExAC

AF:

0.0397

AC:

4793

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Congenital stationary night blindness 1C

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

0.077

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.053

T;.;.;T;T;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.70

T;T;T;T;T;T

MetaRNN

Benign

0.0013

T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.4

L;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

0.22

N;N;N;.;N;N

REVEL

Benign

0.034

Sift

Benign

0.69

T;T;T;.;T;T

Sift4G

Benign

0.67

T;T;T;T;T;T

Polyphen

0.0010

B;.;.;.;.;.

Vest4

0.054

MPC

0.21

ClinPred

0.0047

GERP RS

2.8

Varity_R

0.053

gMVP

0.20

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