rs3784589

chr15-31002511-C-Achr15-31002511-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BA1

The NM_001252024.2(TRPM1):c.4189G>T(p.Glu1397Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0604 in 1,614,030 control chromosomes in the GnomAD database, including 3,520 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E1397E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.065 (368 hom., cov: 32)
  • Exomes 𝑓: 0.060 (3152 hom.)
• Consequence: TRPM1 NM_001252024.2 stop_gained
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.20

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 -12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.141 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• BP6: Variant 15-31002511-C-A is Benign according to our data. Variant chr15-31002511-C-A is described in ClinVar as [Benign]. Clinvar id is 315498.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	UniProt
TRPM1	NM_001252024.2	c.4189G>T	p.Glu1397Ter	stop_gained	28/28	ENST00000256552.11
TRPM1	NM_001252020.2	c.4240G>T	p.Glu1414Ter	stop_gained	27/27
TRPM1	NM_002420.6	c.4123G>T	p.Glu1375Ter	stop_gained	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM1	ENST00000256552.11	c.4189G>T	p.Glu1397Ter	stop_gained	28/28	1	NM_001252024.2	P4
	ENST00000665655.1	n.71+10270C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0644 AC: 9799 AN: 152068 Hom.: 364 Cov.: 32

Gnomad AFR AF: 0.0752

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.0462

Gnomad ASJ AF: 0.0620

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0768

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0585

Gnomad OTH AF: 0.0679

GnomAD3 exomes AF: 0.0632 AC: 15773 AN: 249512 Hom.: 681 AF XY: 0.0679 AC XY: 9195 AN XY: 135378

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: 0.0693

Gnomad NFE exome AF: 0.0582

Gnomad OTH exome AF: 0.0650

GnomAD4 exome AF: 0.0599 AC: 87603 AN: 1461846 Hom.: 3152 Cov.: 34 AF XY: 0.0625 AC XY: 45449 AN XY: 727220

Gnomad4 AFR exome AF: 0.0770

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: 9820 AN: 152184 Hom.: 368 Cov.: 32 AF XY: 0.0660 AC XY: 4911 AN XY: 74406

Gnomad4 AFR AF: 0.0755

Gnomad4 AMR AF: 0.0460

Gnomad4 ASJ AF: 0.0620

Gnomad4 EAS AF: 0.0159

Gnomad4 SAS AF: 0.125

Gnomad4 FIN AF: 0.0768

Gnomad4 NFE AF: 0.0585

Gnomad4 OTH AF: 0.0672

Alfa AF: 0.0557 Hom.: 539

Bravo AF: 0.0603

TwinsUK AF: 0.0550 AC: 204

ALSPAC AF: 0.0547 AC: 211

ESP6500AA AF: 0.0793 AC: 293

ESP6500EA AF: 0.0565 AC: 463

ExAC AF: 0.0653 AC: 7888

Asia WGS AF: 0.0680 AC: 235 AN: 3478

EpiCase AF: 0.0590

EpiControl AF: 0.0557

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital stationary night blindness 1C Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	38
Dann	Uncertain	0.98
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	D;D;D;D
Vest4		0.58
GERP RS		5.0

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

Other links and lift over

dbSNP: rs3784589; hg19: chr15-31294714; COSMIC: COSV56635933;