rs1035705

Variant names:

• chr15-31050541-C-T
• rs1035705
• NM_001252024.2:c.1305G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-31050541-C-T
• chr15-31050541-C-A
• chr15-31050541-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001252024.2(TRPM1):​c.1305G>A​(p.Thr435Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.55 in 1,613,692 control chromosomes in the GnomAD database, including 252,022 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (19500 hom., cov: 31)
  • Exomes 𝑓: 0.56 (232522 hom.)
• Consequence: TRPM1 NM_001252024.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.87
• Publications: 25 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 15-31050541-C-T is Benign according to our data. Variant chr15-31050541-C-T is described in ClinVar as Benign. ClinVar VariationId is 193856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.87 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.919 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.1305G>A	p.Thr435Thr	synonymous	Exon 12 of 28	NP_001238953.1	Q7Z4N2-6
	TRPM1	NM_001252020.2		c.1356G>A	p.Thr452Thr	synonymous	Exon 11 of 27	NP_001238949.1	Q7Z4N2-5
	TRPM1	NM_002420.6		c.1239G>A	p.Thr413Thr	synonymous	Exon 11 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.1305G>A	p.Thr435Thr	synonymous	Exon 12 of 28	ENSP00000256552.7	Q7Z4N2-6
	TRPM1	ENST00000558445.6	TSL:1	c.1356G>A	p.Thr452Thr	synonymous	Exon 11 of 27	ENSP00000452946.2	Q7Z4N2-5
	TRPM1	ENST00000397795.7	TSL:1	c.1239G>A	p.Thr413Thr	synonymous	Exon 11 of 27	ENSP00000380897.2	Q7Z4N2-1

Frequencies

GnomAD3 genomes AF: 0.480 AC: 72871 AN: 151764 Hom.: 19503 Cov.: 31

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.574

Gnomad ASJ AF: 0.566

Gnomad EAS AF: 0.941

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.505

GnomAD2 exomes AF: 0.555 AC: 136961 AN: 246920 AF XY: 0.550

Gnomad AFR exome AF: 0.227

Gnomad AMR exome AF: 0.600

Gnomad ASJ exome AF: 0.559

Gnomad EAS exome AF: 0.963

Gnomad FIN exome AF: 0.541

Gnomad NFE exome AF: 0.546

Gnomad OTH exome AF: 0.561

GnomAD4 exome AF: 0.558 AC: 815022 AN: 1461810 Hom.: 232522 Cov.: 70 AF XY: 0.556 AC XY: 404090 AN XY: 727212

African (AFR) AF: 0.214 AC: 7181 AN: 33480

American (AMR) AF: 0.599 AC: 26778 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.562 AC: 14700 AN: 26136

East Asian (EAS) AF: 0.909 AC: 36095 AN: 39696

South Asian (SAS) AF: 0.478 AC: 41213 AN: 86258

European-Finnish (FIN) AF: 0.540 AC: 28815 AN: 53398

Middle Eastern (MID) AF: 0.463 AC: 2673 AN: 5768

European-Non Finnish (NFE) AF: 0.561 AC: 623961 AN: 1111974

Other (OTH) AF: 0.556 AC: 33606 AN: 60390

GnomAD4 genome AF: 0.480 AC: 72893 AN: 151882 Hom.: 19500 Cov.: 31 AF XY: 0.483 AC XY: 35854 AN XY: 74234

African (AFR) AF: 0.235 AC: 9716 AN: 41418

American (AMR) AF: 0.574 AC: 8762 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.566 AC: 1962 AN: 3468

East Asian (EAS) AF: 0.941 AC: 4850 AN: 5156

South Asian (SAS) AF: 0.505 AC: 2423 AN: 4794

European-Finnish (FIN) AF: 0.542 AC: 5720 AN: 10548

Middle Eastern (MID) AF: 0.500 AC: 145 AN: 290

European-Non Finnish (NFE) AF: 0.558 AC: 37882 AN: 67926

Other (OTH) AF: 0.505 AC: 1063 AN: 2106

Alfa AF: 0.527 Hom.: 39871

Bravo AF: 0.474

Asia WGS AF: 0.653 AC: 2267 AN: 3478

EpiCase AF: 0.552

EpiControl AF: 0.543

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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.3
DANN	Benign	0.63
PhyloP100		-1.9
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1035705; hg19: chr15-31342744; COSMIC: COSV56632216;