15-31002140-A-T

Variant names:

• chr15-31002140-A-T
• rs12898290
• NM_001252024.2:c.4560T>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.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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. H1520H) has been classified as Likely 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
• Publications: 16 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=0.0013849735).
• BP6: Variant 15-31002140-A-T is Benign according to our data. Variant chr15-31002140-A-T is described in ClinVar as Benign. ClinVar VariationId 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.

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.4560T>A	p.His1520Gln	missense	Exon 28 of 28	NP_001238953.1	Q7Z4N2-6
	TRPM1	NM_001252020.2		c.4611T>A	p.His1537Gln	missense	Exon 27 of 27	NP_001238949.1	Q7Z4N2-5
	TRPM1	NM_002420.6		c.4494T>A	p.His1498Gln	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.4560T>A	p.His1520Gln	missense	Exon 28 of 28	ENSP00000256552.7	Q7Z4N2-6
	TRPM1	ENST00000558445.6	TSL:1	c.4611T>A	p.His1537Gln	missense	Exon 27 of 27	ENSP00000452946.2	Q7Z4N2-5
	TRPM1	ENST00000397795.7	TSL:1	c.4494T>A	p.His1498Gln	missense	Exon 27 of 27	ENSP00000380897.2	Q7Z4N2-1

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

GnomAD2 exomes AF: 0.0632 AC: 15777 AN: 249572 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: 0.0692

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

African (AFR) AF: 0.0771 AC: 2580 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.0714 AC: 1865 AN: 26136

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

South Asian (SAS) AF: 0.131 AC: 11266 AN: 86258

European-Finnish (FIN) AF: 0.0660 AC: 3524 AN: 53406

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

European-Non Finnish (NFE) AF: 0.0554 AC: 61601 AN: 1112010

Other (OTH) AF: 0.0618 AC: 3735 AN: 60396

GnomAD4 genome AF: 0.0645 AC: 9829 AN: 152284 Hom.: 372 Cov.: 32 AF XY: 0.0661 AC XY: 4921 AN XY: 74456

African (AFR) AF: 0.0754 AC: 3134 AN: 41538

American (AMR) AF: 0.0459 AC: 702 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0620 AC: 215 AN: 3468

East Asian (EAS) AF: 0.0160 AC: 83 AN: 5186

South Asian (SAS) AF: 0.124 AC: 601 AN: 4832

European-Finnish (FIN) AF: 0.0770 AC: 817 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0585 AC: 3982 AN: 68028

Other (OTH) AF: 0.0672 AC: 142 AN: 2114

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Congenital stationary night blindness 1C (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-4.6
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.024
Sift	Benign	0.36	T
Sift4G	Benign	0.61	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
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: rs12898290; hg19: chr15-31294343; COSMIC: COSV56634761; COSMIC: COSV56634761;