rs781610444
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate
The NM_001252024.2(TRPM1):c.618+3_618+6del variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
TRPM1
NM_001252024.2 splice_donor_5th_base, intron
NM_001252024.2 splice_donor_5th_base, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.88
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
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Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 15-31067056-CACTT-C is Pathogenic according to our data. Variant chr15-31067056-CACTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 438221.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-31067056-CACTT-C is described in Lovd as [Pathogenic]. Variant chr15-31067056-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.618+3_618+6del | splice_donor_5th_base_variant, intron_variant | ENST00000256552.11 | |||
TRPM1 | NM_001252020.2 | c.669+3_669+6del | splice_donor_5th_base_variant, intron_variant | ||||
TRPM1 | NM_002420.6 | c.552+3_552+6del | splice_donor_5th_base_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRPM1 | ENST00000256552.11 | c.618+3_618+6del | splice_donor_5th_base_variant, intron_variant | 1 | NM_001252024.2 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152166Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249580Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135406
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461880Hom.: 0 AF XY: 0.00000963 AC XY: 7AN XY: 727244
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74324
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 27, 2022 | This sequence change falls in intron 5 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 (rs781610444, gnomAD 0.01%). This variant has been observed in individuals with congenital stationary night blindness (PMID: 27803854, 28041643). It has also been observed to segregate with disease in related individuals. This variant is also known as c.669+3_669+6delAAGT. 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. - |
Congenital stationary night blindness Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Computational scores
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SpliceAI score (max)
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DS_DL_spliceai
Position offset: 7
Find out detailed SpliceAI scores and Pangolin per-transcript scores at