rs200865108
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_017777.4(MKS1):āc.1349T>Cā(p.Ile450Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000343 in 1,614,170 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.0015 ( 0 hom., cov: 32)
Exomes š: 0.00023 ( 1 hom. )
Consequence
MKS1
NM_017777.4 missense
NM_017777.4 missense
Scores
3
13
3
Clinical Significance
Conservation
PhyloP100: 8.85
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 Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.09559041).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MKS1 | NM_017777.4 | c.1349T>C | p.Ile450Thr | missense_variant | 15/18 | ENST00000393119.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MKS1 | ENST00000393119.7 | c.1349T>C | p.Ile450Thr | missense_variant | 15/18 | 1 | NM_017777.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00146 AC: 222AN: 152162Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000417 AC: 104AN: 249558Hom.: 0 AF XY: 0.000414 AC XY: 56AN XY: 135398
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GnomAD4 exome AF: 0.000226 AC: 331AN: 1461890Hom.: 1 Cov.: 31 AF XY: 0.000226 AC XY: 164AN XY: 727246
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GnomAD4 genome ? AF: 0.00146 AC: 223AN: 152280Hom.: 0 Cov.: 32 AF XY: 0.00141 AC XY: 105AN XY: 74458
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:10Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Bardet-Biedl syndrome 13 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 15, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 14, 2021 | - - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 25, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 30, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 11, 2023 | Has been reported in a patient with features of BBS as a single heterozygous variant (Leitch et al., 2008); Has also been reported in a patient from a cohort of patients with inherited retinal disease, potentially with a second variant; however segregation data and specific clinical information was not clearly delineated in this report (Sharon et al., 2020); Published functional studies demonstrate a damaging effect (Leitch et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18327255, 34426522, 31456290, 34573333, 30793526) - |
Meckel syndrome, type 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 14, 2021 | - - |
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 03, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 01, 2022 | Variant summary: MKS1 c.1349T>C (p.Ile450Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 249558 control chromosomes, predominantly at a frequency of 0.0036 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in MKS1 causing Meckel Syndrome Type 1 phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1349T>C has been reported in the literature in at least one heterozygous individual affected with Bardet-Biedl syndrome (e.g. Leitch_2008), but to our knowledge has not been found in individuals with Meckel Syndrome Type 1. Multiple assessments for this variant have been submitted to ClinVar after 2014 with conflicting assessments (likely pathogenic n=1, VUS n=6, likely benign n=1). Based on the evidence outlined above, the variant was classified as likely benign. - |
Bardet-Biedl syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Joubert syndrome 28 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 14, 2021 | - - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
MKS1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 13, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;T
Sift4G
Uncertain
D;D
Polyphen
P;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at