Variant rs386834050 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_017777.4(MKS1):c.472C>T(p.Arg158*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,454,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MKS1
NM_017777.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 2.10

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:

MKS1 (HGNC:):

MKS1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-58214784-G-A is Pathogenic according to our data. Variant chr17-58214784-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 56623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58214784-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MKS1	NM_017777.4 linkuse as main transcript	c.472C>T	p.Arg158*	stop_gained	5/18	ENST00000393119.7	NP_060247.2	Q9NXB0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MKS1	ENST00000393119.7 linkuse as main transcript	c.472C>T	p.Arg158*	stop_gained	5/18	1	NM_017777.4	ENSP00000376827.2		Q9NXB0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000123

AC:

AN:

244582

Hom.:

AF XY:

0.00000751

AC XY:

AN XY:

133102

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1454812

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

723996

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2024

This sequence change creates a premature translational stop signal (p.Arg158*) in the MKS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MKS1 are known to be pathogenic (PMID: 19466712, 24886560, 26490104). This variant is present in population databases (rs386834050, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with MKS1-related conditions (PMID: 17397051). ClinVar contains an entry for this variant (Variation ID: 56623). For these reasons, this variant has been classified as Pathogenic. -

Meckel syndrome, type 1

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

- -

Bardet-Biedl syndrome 13

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 14, 2024

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

The R158X variant in the MKS1 gene has been reported previously in association with Meckel syndrome. (Khaddour et al., 2007; Tallila et al., 2009). In one publication, this variant was confirmed to be on the opposite allele (in trans) with another pathogenic variant (Khaddour et al., 2007). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R158X variant is observed in 2/241314 alleles in large population cohorts (Lek et al., 2016). We interpret R158X as a pathogenic variant. -

MKS1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 18, 2024

The MKS1 c.472C>T variant is predicted to result in premature protein termination (p.Arg158*). This variant has been reported in the compound heterozygous state in a fetus with features consistent with Meckel syndrome (Khaddour et al. 2007. PubMed ID: 17397051) and was also reported in the compound heterozygous state in an individual with isolated retinitis pigmentosa who was found to have a mild presentation of Joubert syndrome through molecular testing (Brunetti-Pierri R et al. 2021. PubMed ID: 34359301). Functional studies using HEK293 cells and fibroblasts from the compound heterozygous patient in the Khaddour et al. paper show that these variants result in ciliary defects, deregulation of proteasome, and disrupt Wnt/beta-catenin signaling (Szymanska et al. 2022. PubMed ID: 35170427). This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD. Nonsense variants in MKS1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.86

Vest4

0.93

GERP RS

5.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

Details are displayed if max score is > 0.2

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