rs3784589

Variant names:

• chr15-31002511-C-A
• rs3784589
• NM_001252024.2:c.4189G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-31002511-C-A
• chr15-31002511-C-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BA1

The NM_001252024.2(TRPM1):​c.4189G>T​(p.Glu1397*) 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:4
• Conservation: PhyloP100: 2.20
• Publications: 31 publications found

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 Gene-Disease associations (from GenCC):

• congenital stationary night blindness 1C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• TRPM1-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital stationary night blindness

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000259720 (HGNC:58477):

ACMG classification

Our verdict: Benign. The variant received -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 2 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001252024.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM1	NM_001252024.2	MANE Select	c.4189G>T	p.Glu1397*	stop_gained	Exon 28 of 28	NP_001238953.1	Q7Z4N2-6
	TRPM1	NM_001252020.2		c.4240G>T	p.Glu1414*	stop_gained	Exon 27 of 27	NP_001238949.1	Q7Z4N2-5
	TRPM1	NM_002420.6		c.4123G>T	p.Glu1375*	stop_gained	Exon 27 of 27	NP_002411.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM1	ENST00000256552.11	TSL:1 MANE Select	c.4189G>T	p.Glu1397*	stop_gained	Exon 28 of 28	ENSP00000256552.7	Q7Z4N2-6
	TRPM1	ENST00000558445.6	TSL:1	c.4240G>T	p.Glu1414*	stop_gained	Exon 27 of 27	ENSP00000452946.2	Q7Z4N2-5
	TRPM1	ENST00000397795.7	TSL:1	c.4123G>T	p.Glu1375*	stop_gained	Exon 27 of 27	ENSP00000380897.2	Q7Z4N2-1

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

GnomAD2 exomes AF: 0.0632 AC: 15773 AN: 249512 AF XY: 0.0679

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 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

African (AFR) AF: 0.0770 AC: 2577 AN: 33480

American (AMR) AF: 0.0354 AC: 1584 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0714 AC: 1865 AN: 26134

East Asian (EAS) AF: 0.0219 AC: 871 AN: 39700

South Asian (SAS) AF: 0.131 AC: 11262 AN: 86256

European-Finnish (FIN) AF: 0.0660 AC: 3525 AN: 53390

Middle Eastern (MID) AF: 0.105 AC: 603 AN: 5768

European-Non Finnish (NFE) AF: 0.0554 AC: 61584 AN: 1112000

Other (OTH) AF: 0.0618 AC: 3732 AN: 60394

GnomAD4 genome AF: 0.0645 AC: 9820 AN: 152184 Hom.: 368 Cov.: 32 AF XY: 0.0660 AC XY: 4911 AN XY: 74406

African (AFR) AF: 0.0755 AC: 3134 AN: 41510

American (AMR) AF: 0.0460 AC: 704 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0620 AC: 215 AN: 3466

East Asian (EAS) AF: 0.0159 AC: 82 AN: 5172

South Asian (SAS) AF: 0.125 AC: 601 AN: 4826

European-Finnish (FIN) AF: 0.0768 AC: 813 AN: 10590

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0585 AC: 3975 AN: 68006

Other (OTH) AF: 0.0672 AC: 142 AN: 2112

Alfa AF: 0.0576 Hom.: 1089

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Congenital stationary night blindness 1C (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.2
Vest4		0.58
GERP RS		5.0
Mutation Taster		=177/23	polymorphism (auto)

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

Other links and lift over

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