rs12898290

Positions:

• chr15-31002140-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001252024.2(TRPM1):​c.4560T>A​(p.His1520Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0604 in 1,614,162 control chromosomes in the GnomAD database, including 3,524 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 0.065 (372 hom., cov: 32)
  • Exomes 𝑓: 0.060 (3152 hom.)
• Consequence: TRPM1 NM_001252024.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.60

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013849735).
• BP6: Variant 15-31002140-A-T is Benign according to our data. Variant chr15-31002140-A-T is described in ClinVar as [Benign]. Clinvar id is 315490.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	Protein	UniProt
TRPM1	NM_001252024.2	c.4560T>A	p.His1520Gln	missense_variant	28/28	ENST00000256552.11	NP_001238953.1
TRPM1	NM_001252020.2	c.4611T>A	p.His1537Gln	missense_variant	27/27		NP_001238949.1
TRPM1	NM_002420.6	c.4494T>A	p.His1498Gln	missense_variant	27/27		NP_002411.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM1	ENST00000256552.11	c.4560T>A	p.His1520Gln	missense_variant	28/28	1	NM_001252024.2	ENSP00000256552	P4
	ENST00000665655.1	n.71+9899A>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0645 AC: 9808 AN: 152166 Hom.: 368 Cov.: 32

Gnomad AFR AF: 0.0751

Gnomad AMI AF: 0.131

Gnomad AMR AF: 0.0460

Gnomad ASJ AF: 0.0620

Gnomad EAS AF: 0.0160

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.0770

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0586

Gnomad OTH AF: 0.0679

GnomAD3 exomes AF: 0.0632 AC: 15777 AN: 249572 Hom.: 680 AF XY: 0.0679 AC XY: 9199 AN XY: 135402

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: 0.0692

Gnomad NFE exome AF: 0.0582

Gnomad OTH exome AF: 0.0650

GnomAD4 exome AF: 0.0599 AC: 87629 AN: 1461878 Hom.: 3152 Cov.: 35 AF XY: 0.0625 AC XY: 45460 AN XY: 727242

Gnomad4 AFR exome AF: 0.0771

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: 9829 AN: 152284 Hom.: 372 Cov.: 32 AF XY: 0.0661 AC XY: 4921 AN XY: 74456

Gnomad4 AFR AF: 0.0754

Gnomad4 AMR AF: 0.0459

Gnomad4 ASJ AF: 0.0620

Gnomad4 EAS AF: 0.0160

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.0770

Gnomad4 NFE AF: 0.0585

Gnomad4 OTH AF: 0.0672

Alfa AF: 0.0575 Hom.: 228

Bravo AF: 0.0603

TwinsUK AF: 0.0553 AC: 205

ALSPAC AF: 0.0545 AC: 210

ESP6500AA AF: 0.0755 AC: 309

ESP6500EA AF: 0.0560 AC: 469

ExAC AF: 0.0652 AC: 7891

Asia WGS AF: 0.0680 AC: 235 AN: 3478

EpiCase AF: 0.0591

EpiControl AF: 0.0557

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

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	GeneDx	Aug 05, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Congenital stationary night blindness 1C Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.0010
DANN	Benign	0.59
DEOGEN2	Benign	0.066	T;.;.;T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.29	T;T;T;T
MetaRNN	Benign	0.0014	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.24	N;N;N;.
REVEL	Benign	0.024
Sift	Benign	0.36	T;T;T;.
Sift4G	Benign	0.61	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.017
MutPred		0.16		Gain of helix (P = 0.0199);.;.;.;
MPC		0.21
ClinPred		0.018	T
GERP RS		-10
Varity_R		0.041
gMVP		0.11

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: rs12898290; hg19: chr15-31294343; COSMIC: COSV56634761; COSMIC: COSV56634761;