rs199874059
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The ENST00000393119.7(MKS1):c.1024+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.000036 in 1,612,798 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 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 0 hom. )
Consequence
MKS1
ENST00000393119.7 splice_donor
ENST00000393119.7 splice_donor
Scores
3
3
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 3.67
Genes affected
MKS1 (HGNC:7121): (MKS transition zone complex subunit 1) The protein encoded by this gene localizes to the basal body and is required for formation of the primary cilium in ciliated epithelial cells. Mutations in this gene result in Meckel syndrome type 1 and in Bardet-Biedl syndrome type 13. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.038690478 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-58210658-C-T is Pathogenic according to our data. Variant chr17-58210658-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58210658-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MKS1 | NM_017777.4 | c.1024+1G>A | splice_donor_variant | ENST00000393119.7 | NP_060247.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MKS1 | ENST00000393119.7 | c.1024+1G>A | splice_donor_variant | 1 | NM_017777.4 | ENSP00000376827 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152176Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000601 AC: 15AN: 249484Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135356
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GnomAD4 exome AF: 0.0000377 AC: 55AN: 1460504Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24AN XY: 726686
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152294Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74470
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Meckel syndrome, type 1 Pathogenic:2
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2007 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 17, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 08, 2021 | Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17377820, 25525159) - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change affects a donor splice site in intron 11 of the MKS1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MKS1 are known to be pathogenic (PMID: 19466712, 24886560, 26490104). This variant is present in population databases (rs199874059, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with Meckel-Gruber syndrome (PMID: 17377820). 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 IVS11+1G>A. ClinVar contains an entry for this variant (Variation ID: 1391). 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. - |
Bardet-Biedl syndrome 13 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 06, 2024 | - - |
Bardet-Biedl syndrome 13;C3714506:Meckel syndrome, type 1;C4310705:Joubert syndrome 28 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 07, 2017 | - - |
MKS1-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 11, 2024 | The MKS1 c.1024+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in an individual with Meckel syndrome (Consugar et al. 2007. PubMed ID: 17377820). This variant has not been reported in a large population database, indicating this variant is rare. Variants that disrupt the consensus splice donor site in MKS1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
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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