rs761620701
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1_StrongPM2PP3_StrongPP5_Very_Strong
The NM_015166.4(MLC1):c.714+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.0000112 in 1,610,832 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
MLC1
NM_015166.4 splice_donor
NM_015166.4 splice_donor
Scores
3
3
1
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 6.84
Genes affected
MLC1 (HGNC:17082): (modulator of VRAC current 1) The function of this gene product is unknown; however, homology to other proteins suggests that it may be an integral membrane transporter. Mutations in this gene have been associated with megalencephalic leukoencephalopathy with subcortical cysts, an autosomal recessive neurological disorder. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.10229277 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 22-50074215-C-T is Pathogenic according to our data. Variant chr22-50074215-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLC1 | NM_015166.4 | c.714+1G>A | splice_donor_variant | ENST00000311597.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLC1 | ENST00000311597.10 | c.714+1G>A | splice_donor_variant | 1 | NM_015166.4 | P1 | |||
MLC1 | ENST00000395876.6 | c.714+1G>A | splice_donor_variant | 1 | P1 | ||||
MLC1 | ENST00000442311.1 | c.624+1G>A | splice_donor_variant | 5 | |||||
MLC1 | ENST00000470008.1 | n.194+1G>A | splice_donor_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000285 AC: 7AN: 245280Hom.: 0 AF XY: 0.0000301 AC XY: 4AN XY: 133066
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GnomAD4 exome AF: 0.0000117 AC: 17AN: 1458690Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 725512
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74338
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Megalencephalic leukoencephalopathy with subcortical cysts 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Sep 24, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 15, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 22, 2023 | ClinVar contains an entry for this variant (Variation ID: 188980). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MLC1 protein in which other variant(s) (p.Gly212Arg) have been determined to be pathogenic (PMID: 11254442, 21145992, 27322623). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Studies have shown that disruption of this splice site results in skipping of 9, but is expected to preserve the integrity of the reading-frame (PMID: 16652334). Disruption of this splice site has been observed in individual(s) with megalencephalic leukoencephalopathy with subcortical cysts (PMID: 16652334). This variant is present in population databases (rs761620701, gnomAD 0.02%). This sequence change affects a donor splice site in intron 8 of the MLC1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D
GERP RS
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at