rs199832333

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017777.4(MKS1):c.118C>T(p.His40Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000657 in 1,614,002 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00042 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00068 ( 0 hom. )

Consequence

MKS1
NM_017777.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 4.80

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:

LPO (HGNC:6678): (lactoperoxidase) This gene encodes a member of the peroxidase family of proteins. The encoded preproprotein is proteolytically processed to generate the mature enzyme. Following its secretion from salivary, mammary, and other mucosal glands, this enzyme catalyzes the generation of the antimicrobial substance hypothiocyanous acid. This gene is present in a gene cluster on chromosome 17. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

LPO links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MKS1	NM_017777.4 linkuse as main transcript	c.118C>T	p.His40Tyr	missense_variant	2/18	ENST00000393119.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MKS1	ENST00000393119.7 linkuse as main transcript	c.118C>T	p.His40Tyr	missense_variant	2/18	1	NM_017777.4	P1	Q9NXB0-1

Frequencies

GnomAD3 genomes

AF:

0.000421

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000397

AC:

AN:

249588

Hom.:

AF XY:

0.000450

AC XY:

AN XY:

135410

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000928

Gnomad NFE exome

AF:

0.000777

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000681

AC:

996

AN:

1461752

Hom.:

Cov.:

AF XY:

0.000696

AC XY:

506

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000848

Gnomad4 OTH exome

AF:

0.000596

GnomAD4 genome

AF:

0.000420

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0225

Hom.:

2344

Bravo

AF:

0.000589

ESP6500AA

AF:

0.000504

AC:

ESP6500EA

AF:

0.000839

AC:

ExAC

AF:

0.000413

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 18, 2021

DNA sequence analysis of the MKS1 gene demonstrated a sequence change, c.118C>T, in exon 2 that results in an amino acid change, p.His40Tyr. This sequence change has been described in gnomAD with a frequency of 0.072% in the Non-Finnish European sub-population (dbSNP rs199832333). The p.His40Tyr change affects a moderately conserved amino acid residue located in a domain of the MKS1 protein that is not known to be functional. The p.His40Tyr substitution appears to be tolerated using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in patients with MKS1-related disorders. Due to the lack of sufficient evidences, the clinical significance of the p.His40Tyr change remains unknown at this time. -

Meckel syndrome, type 1

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

MKS1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 23, 2024

The MKS1 c.118C>T variant is predicted to result in the amino acid substitution p.His40Tyr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.072% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is likely too common for an undocumented disease-causing variant. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.33

Cadd

Benign

Dann

Benign

0.94

DEOGEN2

Benign

0.21

T;T;.

Eigen

Benign

-0.088

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.045

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.4

L;.;.

MutationTaster

Benign

1.0

D;N;N;N;N;D

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.53

N;.;N

REVEL

Benign

0.14

Sift

Benign

1.0

T;.;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.13

B;.;.

Vest4

0.25

MVP

0.72

MPC

0.30

ClinPred

0.039

GERP RS

5.3

Varity_R

0.090

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.27

Position offset: 37

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