Variant rs386834043 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_017777.4(MKS1):c.1408-34_1408-6del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,611,528 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 0 hom. )

Consequence

MKS1
NM_017777.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 3.22

Variant links:

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]

MKS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-58206552-GGCATGCCATTGGGACAGCCTCAGGTTTCT-G is Pathogenic according to our data. Variant chr17-58206552-GGCATGCCATTGGGACAGCCTCAGGTTTCT-G is described in ClinVar as [Pathogenic]. Clinvar id is 188400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58206552-GGCATGCCATTGGGACAGCCTCAGGTTTCT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MKS1	NM_017777.4 linkuse as main transcript	c.1408-34_1408-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000393119.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MKS1	ENST00000393119.7 linkuse as main transcript	c.1408-34_1408-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_017777.4	P1	Q9NXB0-1

Frequencies

GnomAD3 genomes

AF:

0.00120

AC:

183

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00885

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00113

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00105

AC:

260

AN:

246468

Hom.:

AF XY:

0.000949

AC XY:

127

AN XY:

133848

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00678

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.00110

AC:

1602

AN:

1459406

Hom.:

AF XY:

0.00107

AC XY:

779

AN XY:

726056

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00748

Gnomad4 NFE exome

AF:

0.00105

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.00120

AC:

183

AN:

152122

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

105

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.000266

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00885

Gnomad4 NFE

AF:

0.00113

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000790

Hom.:

Bravo

AF:

0.000582

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Meckel syndrome, type 1

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 24, 2019	NM_017777.3(MKS1):c.1408-34_1408-6del29 is classified as pathogenic in the context of MKS1-related disorders. Sources cited for classification include the following: PMID 16415886 and 23351400. Classification of NM_017777.3(MKS1):c.1408-34_1408-6del29 is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2007	- -
Pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 20, 2023	Variant summary: MKS1 c.1408-34_1408-6del29 alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 3 prime acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0011 in 246468 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MKS1 causing Meckel Syndrome Type 1, allowing no conclusion about variant significance. c.1408-34_1408-6del29 has been reported in the literature in individuals affected with Meckel Syndrome Type 1. These data indicate that the variant is likely to be associated with disease. Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic n=11, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 29, 2019	DNA sequence analysis of the MKS1 gene demonstrated a 29 bp-deletion in intron 15, c.1408-34_1408-6del. This intronic change is a founder mutation in the Finnish population and a known cause of Meckel-Gruber syndrome. It has been reported in the homozygous and compound heterozygous state in multiple affected individuals (PMIDs: 16415886, 17935508, 17397051). Functional studies in an affected individual's fibroblasts have demonstrated that this variant disrupts mRNA splicing leading to a premature stop codon and a truncated or absent protein (PMID: 16415886). -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 11, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2022	Described as a founder mutation in the Finnish population and many other European populations (Kyttala et al., 2006; Frank et al., 2007); Published functional studies demonstrate abnormal gene splicing (Kyttala et al., 2006); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17377820, 23351400, 17437276, 17935508, 16415886, 17397051, 27377014, 29096034) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 16, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	MKS1: PM3:Very Strong, PM2, PP3, PS3:Supporting -

Joubert syndrome 28

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Apr 08, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Nov 29, 2017	- -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

This sequence change falls in intron 15 of the MKS1 gene. It does not directly change the encoded amino acid sequence of the MKS1 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs749737706, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with Meckel-Gruber syndrome (PMID: 16415886, 17377820, 17397051, 17437276, 17935508). It is commonly reported in individuals of Finnish ancestry (PMID: 23351400). ClinVar contains an entry for this variant (Variation ID: 188400). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 16 and introduces a new termination codon (PMID: 16415886). However the mRNA is not expected to undergo nonsense-mediated decay. 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

Oct 31, 2023

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.1408-34_1408-6del29 alteration is located in intron 15 of the MKS1 gene. This alteration consists of a deletion of 29 nucleotides at nucleotide position c.1408-34 to c.1408-6. This mutation has been identified in the homozygous state in multiple Meckel syndrome families and is considered a founder mutation in the Finnish population (Kyttälä, 2006). It has also been reported in several other individuals in the homozygous or compound heterozygous state with Meckel syndrome or a MKS1-related ciliopathy (Consugar, 2007; Szymanska, 2012; Bader, 2016). Analysis of fibroblasts from an individual homozygous for this mutation demonstrated aberrant splicing (Kyttälä, 2006). Based on the available evidence, this alteration is classified as pathogenic. -

MKS1-related condition

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2024

The MKS1 c.1408-34_1408-6del29 variant is predicted to result in an intronic deletion. This deletion has been shown to disrupt splicing of MKS1 and cause Meckel-Gruber syndrome in multiple unrelated individuals when found in the homozygous or compound heterozygous states (reported as IVS15-7_35del in Table 1, Kyttala et al. 2006. PubMed ID: 16415886; reported as c.1408-35_1408-7del29, Szymanska et al. 2012. PubMed ID: 23351400). This variant is reported in 0.70% of alleles in individuals of European (Finnish) descent in gnomAD. In ClinVar, this variant is reported as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/188400/). This variant is interpreted as pathogenic. -

Familial aplasia of the vermis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Universitätsklinikum Salzburg, Universitätskinderklinik

Jun 19, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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