rs3784588

Variant names:

• chr15-31002451-C-T
• rs3784588
• NM_001252024.2:c.4249G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001252024.2(TRPM1):​c.4249G>A​(p.Val1417Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0651 in 1,614,154 control chromosomes in the GnomAD database, including 4,382 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (374 hom., cov: 33)
  • Exomes 𝑓: 0.066 (4008 hom.)
• Consequence: TRPM1 NM_001252024.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.677
• Publications: 26 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: Labcorp Genetics (formerly Invitae), G2P
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011872351).
• BP6: Variant 15-31002451-C-T is Benign according to our data. Variant chr15-31002451-C-T is described in ClinVar as Benign. ClinVar VariationId is 315496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.126 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.4249G>A	p.Val1417Ile	missense	Exon 28 of 28	NP_001238953.1	Q7Z4N2-6
	TRPM1	NM_001252020.2		c.4300G>A	p.Val1434Ile	missense	Exon 27 of 27	NP_001238949.1	Q7Z4N2-5
	TRPM1	NM_002420.6		c.4183G>A	p.Val1395Ile	missense	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.4249G>A	p.Val1417Ile	missense	Exon 28 of 28	ENSP00000256552.7	Q7Z4N2-6
	TRPM1	ENST00000558445.6	TSL:1	c.4300G>A	p.Val1434Ile	missense	Exon 27 of 27	ENSP00000452946.2	Q7Z4N2-5
	TRPM1	ENST00000397795.7	TSL:1	c.4183G>A	p.Val1395Ile	missense	Exon 27 of 27	ENSP00000380897.2	Q7Z4N2-1

Frequencies

GnomAD3 genomes AF: 0.0573 AC: 8716 AN: 152164 Hom.: 369 Cov.: 33

Gnomad AFR AF: 0.0239

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0220

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0562

Gnomad OTH AF: 0.0695

GnomAD2 exomes AF: 0.0833 AC: 20796 AN: 249536 AF XY: 0.0828

Gnomad AFR exome AF: 0.0216

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.116

Gnomad FIN exome AF: 0.0219

Gnomad NFE exome AF: 0.0593

Gnomad OTH exome AF: 0.0777

GnomAD4 exome AF: 0.0659 AC: 96409 AN: 1461872 Hom.: 4008 Cov.: 36 AF XY: 0.0674 AC XY: 49029 AN XY: 727242

African (AFR) AF: 0.0228 AC: 762 AN: 33480

American (AMR) AF: 0.169 AC: 7552 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 3042 AN: 26136

East Asian (EAS) AF: 0.0850 AC: 3376 AN: 39700

South Asian (SAS) AF: 0.120 AC: 10314 AN: 86256

European-Finnish (FIN) AF: 0.0241 AC: 1289 AN: 53418

Middle Eastern (MID) AF: 0.108 AC: 621 AN: 5768

European-Non Finnish (NFE) AF: 0.0585 AC: 65044 AN: 1111994

Other (OTH) AF: 0.0730 AC: 4409 AN: 60396

GnomAD4 genome AF: 0.0573 AC: 8729 AN: 152282 Hom.: 374 Cov.: 33 AF XY: 0.0584 AC XY: 4349 AN XY: 74470

African (AFR) AF: 0.0239 AC: 992 AN: 41574

American (AMR) AF: 0.131 AC: 1996 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 374 AN: 3464

East Asian (EAS) AF: 0.109 AC: 563 AN: 5186

South Asian (SAS) AF: 0.118 AC: 568 AN: 4828

European-Finnish (FIN) AF: 0.0220 AC: 233 AN: 10612

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0562 AC: 3825 AN: 68014

Other (OTH) AF: 0.0693 AC: 146 AN: 2108

Alfa AF: 0.0610 Hom.: 726

Bravo AF: 0.0630

TwinsUK AF: 0.0615 AC: 228

ALSPAC AF: 0.0581 AC: 224

ESP6500AA AF: 0.0213 AC: 80

ESP6500EA AF: 0.0554 AC: 456

ExAC AF: 0.0786 AC: 9503

Asia WGS AF: 0.115 AC: 399 AN: 3478

EpiCase AF: 0.0635

EpiControl AF: 0.0656

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Congenital stationary night blindness 1C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.5
DANN	Benign	0.48
DEOGEN2	Benign	0.067	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.68
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.047
Sift	Benign	0.78	T
Sift4G	Benign	0.58	T
Polyphen		0.0020	B
Vest4		0.023
MPC		0.17
ClinPred		0.00035	T
GERP RS		1.1
Varity_R		0.024
gMVP		0.094
Mutation Taster		=100/0	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: rs3784588; hg19: chr15-31294654; COSMIC: COSV56634405; COSMIC: COSV56634405;