rs386834050

chr17-58214784-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_017777.4(MKS1):c.472C>T(p.Arg158Ter) 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.10

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]

ACMG classification

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	UniProt
MKS1	NM_017777.4	c.472C>T	p.Arg158Ter	stop_gained	5/18	ENST00000393119.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MKS1	ENST00000393119.7	c.472C>T	p.Arg158Ter	stop_gained	5/18	1	NM_017777.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000123 AC: 3 AN: 244582 Hom.: 0 AF XY: 0.00000751 AC XY: 1 AN XY: 133102

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: 4 AN: 1454812 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 723996

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.: 32

Bravo AF: 0.0000113

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

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

Oct 14, 2022

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	36
Dann	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.86	D
MutationTaster	Benign	1.0	A;A;A;A;D
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

Other links and lift over

dbSNP: rs386834050; hg19: chr17-56292145;