rs386834048

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_017777.4(MKS1):c.417G>A(p.Glu139=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.000152 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

MKS1
NM_017777.4 splice_region, synonymous

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17U:1

Conservation

PhyloP100: 6.25

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 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant 17-58216088-C-T is Pathogenic according to our data. Variant chr17-58216088-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58216088-C-T is described in Lovd as [Pathogenic]. Variant chr17-58216088-C-T is described in Lovd as [Likely_pathogenic]. Variant chr17-58216088-C-T 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.417G>A	p.Glu139=	splice_region_variant, synonymous_variant	4/18	ENST00000393119.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MKS1	ENST00000393119.7 linkuse as main transcript	c.417G>A	p.Glu139=	splice_region_variant, synonymous_variant	4/18	1	NM_017777.4	P1	Q9NXB0-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000128

AC:

AN:

249574

Hom.:

AF XY:

0.000148

AC XY:

AN XY:

135404

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000238

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000155

AC:

226

AN:

1461844

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

110

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.000650

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000176

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000125

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.0000945

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 20, 2022	- -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Mar 14, 2016	- -

Meckel syndrome, type 1

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 01, 2023	Variant summary: MKS1 c.417G>A (p.Glu139Glu) alters a conserved 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: Two predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant indeed affects mRNA splicing, leading to the skipping of exon 4 which results in an in-frame deletion (p.Phe88_Glu139del) (Consugar_2007). The variant allele was found at a frequency of 0.00013 in 249574 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MKS1 causing Meckel Syndrome Type 1 (0.00013 vs 0.0011), allowing no conclusion about variant significance. c.417G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Meckel Syndrome Type 1, including one homozygote and at least three cases where it was found in trans with a pathogenic variant (e.g. Frank_2007, Consugar_2007, Khaddour_2007, Meier_2019). The variant has also been reported in at least one individual affected with Joubert syndrome (e.g. Bachmann-Gagescu_2015). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 26092869, 17377820, 17437276, 17397051, 30679815, 26490104, 28497568, 19466712). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either pathogenic (n=2)/likely pathogenic (n=4) or VUS (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 11, 2018	The MKS1 c.417G>A (p.Glu139Glu) variant has been reported in three studies in probands with Meckel syndrome (MKS) in which it is found in a total of four individuals, all in a compound heterozygous state with a second pathogenic variant (Consugar et al. 2007; Khaddour et al. 2007; Frank et al. 2007). The p.Glu139Glu variant was absent from 410 control chromosomes but is reported at a frequency of 0.000394 in the Ashkenazi Jewish population of the Genome Aggregation Database. The p.Glu139Glu variant is a synonymous variant that affects the last nucleotide of exon four and is predicted to destroy the splice donor site. RT-PCR and sequence analysis of proband fibroblasts showed a smaller abnormal band which when sequenced, confirmed that the variant results in skipping of exon 4 (Consugar et al. 2007). Aberrant splicing is a known mechanism in MKS. Based on the evidence, the p.Glu139Glu variant is classified as likely pathogenic for Meckel syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
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	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

This sequence change affects codon 139 of the MKS1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MKS1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs386834048, gnomAD 0.04%). This variant has been observed in individual(s) with Meckel syndrome or Joubert syndrome (PMID: 17377820, 17397051, 17437276, 26092869, 26490104, 28497568). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1392). 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 4, but is expected to preserve the integrity of the reading-frame (PMID: 17377820). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2021

The c.417G>A (p.E139E) alteration is located in coding exon 4 of the MKS1 gene. This alteration consists of a G to A substitution at nucleotide position 417. This nucleotide substitution does not change the glutamic acid at codon 139. However, this change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing. This variant has been identified in individuals with Meckel syndrome as well as Joubert syndrome in conjunction with a second MKS1 variant (Frank, 2007; Khaddour, 2007; Consugar, 2007; Bachmann-Gagescu, 2015; Summers, 2017). RT-PCR of fibroblasts from an individual with Meckel syndrome and this variant demonstrated exon skipping (Consugar, 2007). In silico splice site analysis predicts that this alteration may weaken the native splice donor site. Based on the available evidence, this alteration is classified as likely pathogenic. -

Bardet-Biedl syndrome 13

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 25, 2023

- -

Bardet-Biedl syndrome 13;C3714506:Meckel syndrome, type 1;C4310705:Joubert syndrome 28

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Apr 24, 2017

- -

Meckel-Gruber syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 31, 2017

The p.Glu139Glu (NM_017777.3 c.417G>A) variant in MKS1 has been reported in 8 co mpound heterozygous individuals with Meckel syndrome and 1 compound heterozygous individual with Joubert syndrome (Consugar 2007, Khaddour 2007, Frank 2007, Tal lila 2009, Bachmann-Gagescu 2015). This variant is located in the last base of t he exon, which is part of the 5? splice region, and has been demonstrated to imp act splicing in patient cells (Consugar 2007). It has been identified in 31/126, 722 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnom ad.broadinstitute.org; dbSNP rs386834048, rs370514840). Although this variant ha s been seen in the general population, its frequency is low enough to be consist ent with a recessive carrier frequency. Biallelic loss of function of the MKS1 g ene is associated with Meckel syndrome and Joubert syndrome. In summary, the p. Glu139Glu variant is likely pathogenic for Meckel syndrome in an autosomal reces sive manner based on its occurrence in affected individuals and demonstrated imp act on splicing. -

MKS1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 25, 2023

The MKS1 c.417G>A is a noncoding alteration. This variant is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). This variant has been reported in individuals with Joubert syndrome (Table S5, Bachmann-Gagescu et al. 2015. PubMed ID: 26092869; Supplemental Table II, Summers et al. 2017. PubMed ID: 28497568) and Meckel syndrome (Consugar et al. 2007. PubMed ID: 17377820; Meier et al. 2019. PubMed ID: 30679815). mRNA studies in affected individual's fibroblasts confirmed that this variant results in the skipping of exon 4 (Consugar et al. 2007. PubMed ID: 17377820). This variant is reported in 0.039% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-56293449-C-T). This variant is interpreted as likely pathogenic. -

Familial aplasia of the vermis

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

UW Hindbrain Malformation Research Program, University of Washington

Feb 23, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.14

Cadd

Benign

Dann

Benign

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.42

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.42

Position offset: 0

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

Other links and lift over