rs104886461
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_020533.3(MCOLN1):c.406-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000105 in 1,613,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_020533.3 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152192Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000207 AC: 52AN: 251204Hom.: 0 AF XY: 0.000206 AC XY: 28AN XY: 135828
GnomAD4 exome AF: 0.000107 AC: 157AN: 1461560Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 88AN XY: 727084
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152192Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6AN XY: 74338
ClinVar
Submissions by phenotype
Mucolipidosis type IV Pathogenic:7Other:1
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NM_020533.2(MCOLN1):c.406-2A>G(aka IVS3-2A>G) is classified as pathogenic in the context of mucolipidosis IV. Sources cited for classification include the following: PMID 11317355, 11030752, 11013137, 10973263, 16645217, 16287144, 11845410, 17384215, 1471493347. Classification of NM_020533.2(MCOLN1):c.406-2A>G(aka IVS3-2A>G) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Accounts for 77% of pathogenic variants in Ashkenazi Jewish persons. Approximately 60% of individuals with MLIV of Ashkenazi Jewish heritage in the US are homozygotes for the c.406-2A>G intronic acceptor splice site pathogenic variant. An estimated 33% are compound heterozygotes for this variant and the 6.4-kb deletion. -
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This sequence change affects an acceptor splice site in intron 3 of the MCOLN1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs104886461, gnomAD 0.4%). Disruption of this splice site has been observed in individuals with Lisch epithelial corneal dystrophy and/or mucolipidosis type IV (PMID: 11013137, 19815695, 37972748). It is commonly reported in individuals of Ashkenazi ancestry (PMID: 11013137, 19815695). ClinVar contains an entry for this variant (Variation ID: 5131). Studies have shown that disruption of this splice site results in exon 4 skipping, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 11013137). For these reasons, this variant has been classified as Pathogenic. -
The MCOLN1 c.406-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. Across a selection of the available literature, the c.406-2A>G variant has been identified in a homozygous state in 13 probands and six in a compound heterozygous state including one sibling pair with mucolipidosis (Bargal et al. 2000; Bassi et al. 2000). The variant has also been found in unaffected heterozygous carriers. The c.406-2A>G variant is reported at a frequency of 0.004237 in the Ashkenazi Jewish population of the Genome Aggregation Database. The c.406-2A>G variant causes exon skipping which results in a protein predicted to retain only 3.6% of wild type protein (Bassi et al. 2000). Based on the evidence, the c.406-2A>G variant is classified as pathogenic for mucolipidosis, type IV. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
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not provided Pathogenic:3Other:1
Reverse transcription polymerase chain reaction of RNA extracted from individuals affected with mucolipidosis type IV who harbored c.406-2 A>G revealed aberrant spicing (PMID: 10973263); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 21228398, 11845410, 31663226, 10973263, 28392473, 10441585, 19815695, 11013137, 11030752, 11317355, 23891399, 30609409, 31980526, 37972748, 37267771, 35425852, 17384215, 23555759, 16645217, 16287144, 11551108, 15523648) -
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MCOLN1: PM3:Very Strong, PVS1, PM2 -
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Mucolipidosis Pathogenic:1
The c.406-2A>G variant (NM_020433.2) in MCOLN1 has been reported in at least 12 homozygous and 1 compound heterozygous individuals with mucolipidosis type IV (B argal 2000). This variant has also been reported in ClinVar (Variation ID#5131), as pathogenic by multiple laboratories. This variant occurs in the invariant re gion (+/- 1,2) of the splice consensus sequence and has been demonstrated to imp act splicing and lead to skipping of exon 4, introducing a frameshift (Bargal 20 00, Edelmann 2002). This variant has been identified in 0.42% (43/10148) of Ash kenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gno mad.broadinstitute.org; dbSNP rs104886461) and has been reported as a founder mu tation in the Ashkenazi Jewish population (Edelmann 2002, Hantash 2006) . Bialle lic loss of function of the MCOLN1 gene is an established disease mechanism for mucolipidosis type IV. In summary, this variant meets criteria to be classified as pathogenic for mucolipidosis type IV in an autosomal recessive manner based u pon its biallelic occurrence in individuals with this disease and functional imp act on the protein. ACMG/AMP Criteria applied: PVS1, PM3_Strong (upgraded to str ong based on multiple occurrences), PP5. -
Mucolipidosis type IV;C2749050:Lisch epithelial corneal dystrophy Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at