rs772011426

chr15-31062572-CACTT-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001252024.2(TRPM1):c.1089+3_1089+6del variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.00000753 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: TRPM1 NM_001252024.2 splice_donor_5th_base, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.17

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-31062572-CACTT-C is Pathogenic according to our data. Variant chr15-31062572-CACTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 30364.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-31062572-CACTT-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM1	NM_001252024.2	c.1089+3_1089+6del		splice_donor_5th_base_variant, intron_variant		ENST00000256552.11
TRPM1	NM_001252020.2	c.1140+3_1140+6del		splice_donor_5th_base_variant, intron_variant
TRPM1	NM_002420.6	c.1023+3_1023+6del		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM1	ENST00000256552.11	c.1089+3_1089+6del		splice_donor_5th_base_variant, intron_variant		1	NM_001252024.2	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249332 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135280

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461694 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 727158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000102 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital stationary night blindness 1C Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 12, 2010

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

This sequence change falls in intron 8 of the TRPM1 gene. It does not directly change the encoded amino acid sequence of the TRPM1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs772011426, gnomAD 0.01%). This variant has been observed in individual(s) with congenital stationary night blindness (PMID: 20300565; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS8+3_6delAAGT. ClinVar contains an entry for this variant (Variation ID: 30364). Studies have shown that this variant alters TRPM1 gene expression (PMID: 20300565). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs772011426; hg19: chr15-31354775;