Variant rs386834044 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.1453_1454insGGCA(p.Thr485ArgfsTer107) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000266 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T485T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

MKS1
NM_017777.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 4.39

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:

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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 17-58206501-G-GTGCC is Pathogenic according to our data. Variant chr17-58206501-G-GTGCC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MKS1	NM_017777.4 linkuse as main transcript	c.1453_1454insGGCA	p.Thr485ArgfsTer107	frameshift_variant	16/18	ENST00000393119.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MKS1	ENST00000393119.7 linkuse as main transcript	c.1453_1454insGGCA	p.Thr485ArgfsTer107	frameshift_variant	16/18	1	NM_017777.4	P1	Q9NXB0-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000722

AC:

AN:

249270

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

135242

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000588

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461752

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000475

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Meckel syndrome, type 1

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 05, 2016	- -

Bardet-Biedl syndrome 13

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Pediatrics Genetics, Post Graduate Institute of Medical Education and Research	Mar 01, 2023	PVS1, PM2, PP5 -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 24, 2024	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 10, 2023

This sequence change results in a frameshift in the MKS1 gene (p.Thr485Argfs*107). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 75 amino acid(s) of the MKS1 protein and extend the protein by 31 additional amino acid residues. This variant is present in population databases (rs386834044, gnomAD 0.06%). This frameshift has been observed in individual(s) with Meckel Gruber syndrome (PMID: 17185389, 17397051). This variant is also known as c.1448_1451dupCAGG; p.G484fsX108. ClinVar contains an entry for this variant (Variation ID: 56617). This variant results in an extension of the MKS1 protein. Other variant(s) that result in a similarly extended protein product (p.Arg510Profs*81) have been observed in individuals with MKS1-related disease (PMID: 26490104). This suggests that these extensions may be clinically significant. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 20, 2022

- -

Joubert syndrome 28

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Counsyl

Dec 05, 2016

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

May 02, 2021

- -

MKS1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

The MKS1 c.1450_1453dupGGCA (p.Thr485ArgfsTer107) variant, also known as c.1448_1451dupCAGG, results in a frameshift and is predicted to cause an elongation of the protein. Across a selection of available literature, the p.Thr485ArgfsTer107 variant was identified in a homozygous state in four individuals with Meckel syndrome from consanguineous families of Pakistani origin (Dawe et al. 2007; Khaddour et al. 2007; Szymanska et al. 2012). The p.Thr485ArgfsTer107 variant has not been reported in any cases of Bardet-Biedl syndrome. The variant was absent from 96 healthy controls but is reported at a frequency of 0.00067 in the South Asian population of the Exome Aggregation Consortium. Dawe et al. (2007) conducted immunohistochemistry staining in kidney tissue from an affected individual carrying the p.Thr485ArgfsTer107 variant and demonstrated a lack of MKS1 protein compared to age-matched control tissue. Based on the evidence from the literature and potential impact of frameshift variants, the p.Thr485ArgfsTer107 variant is classified as likely pathogenic for MKS1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Familial aplasia of the vermis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 08, 2016

This sequence change inserts 4 nucleotides in exon 16 of the MKS1 mRNA (c.1450_1453dupGGCA), causing a frameshift at codon 485. This creates a premature translational stop signal (p.Thr485Argfs*107) and is expected to result in an absent or disrupted protein product. Truncating variants in MKS1 are known to be pathogenic. This particular truncation has been reported in the homozygous state from an individual affected with Meckel Gruber syndrome in the literature (PMID: 17397051, 17185389). This variant is also known as c.1448_1451dupCAGG; p.G484fsX108 in the literature. For these reasons, this variant has been classified as Pathogenic. -

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

Other links and lift over