rs12911350

chr15-31037741-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001252024.2(TRPM1):c.2541C>T(p.Asn847=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,613,938 control chromosomes in the GnomAD database, including 13,582 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1248 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12334 hom.)
• Consequence: TRPM1 NM_001252024.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.470

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 15-31037741-G-A is Benign according to our data. Variant chr15-31037741-G-A is described in ClinVar as [Benign]. Clinvar id is 315509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.47 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM1	NM_001252024.2	c.2541C>T	p.Asn847=	synonymous_variant	20/28	ENST00000256552.11
TRPM1	NM_001252020.2	c.2592C>T	p.Asn864=	synonymous_variant	19/27
TRPM1	NM_002420.6	c.2475C>T	p.Asn825=	synonymous_variant	19/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM1	ENST00000256552.11	c.2541C>T	p.Asn847=	synonymous_variant	20/28	1	NM_001252024.2	P4

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18468 AN: 152084 Hom.: 1247 Cov.: 33

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.0782

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.110

GnomAD3 exomes AF: 0.129 AC: 32269 AN: 249580 Hom.: 2494 AF XY: 0.128 AC XY: 17348 AN XY: 135406

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.0835

Gnomad EAS exome AF: 0.00834

Gnomad SAS exome AF: 0.116

Gnomad FIN exome AF: 0.170

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.126 AC: 183933 AN: 1461736 Hom.: 12334 Cov.: 34 AF XY: 0.125 AC XY: 91064 AN XY: 727178

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.194

Gnomad4 ASJ exome AF: 0.0874

Gnomad4 EAS exome AF: 0.0217

Gnomad4 SAS exome AF: 0.116

Gnomad4 FIN exome AF: 0.170

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.112

GnomAD4 genome AF: 0.121 AC: 18492 AN: 152202 Hom.: 1248 Cov.: 33 AF XY: 0.124 AC XY: 9204 AN XY: 74428

Gnomad4 AFR AF: 0.109

Gnomad4 AMR AF: 0.155

Gnomad4 ASJ AF: 0.0782

Gnomad4 EAS AF: 0.0106

Gnomad4 SAS AF: 0.111

Gnomad4 FIN AF: 0.164

Gnomad4 NFE AF: 0.127

Gnomad4 OTH AF: 0.111

Alfa AF: 0.127 Hom.: 1669

Bravo AF: 0.121

Asia WGS AF: 0.0720 AC: 254 AN: 3478

EpiCase AF: 0.124

EpiControl AF: 0.129

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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
BayesDel_noAF	Benign	-0.57
Cadd	Benign	0.028
Dann	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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

Other links and lift over

dbSNP: rs12911350; hg19: chr15-31329944; COSMIC: COSV56635643; COSMIC: COSV56635643;