chr17-58212983-T-C

Position:

chr17-58212983-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_017777.4(MKS1):c.857A>G(p.Asp286Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000921 in 1,613,966 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00084 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00093 ( 2 hom. )

Consequence

MKS1
NM_017777.4 missense, splice_region

Scores

Splicing: ADA: 0.9999

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:16

Conservation

PhyloP100: 6.76

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 Likely_benign. Variant got -2 ACMG points.

PP3

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

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MKS1	NM_017777.4 linkuse as main transcript	c.857A>G	p.Asp286Gly	missense_variant, splice_region_variant	8/18	ENST00000393119.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MKS1	ENST00000393119.7 linkuse as main transcript	c.857A>G	p.Asp286Gly	missense_variant, splice_region_variant	8/18	1	NM_017777.4	P1	Q9NXB0-1

Frequencies

GnomAD3 genomes

AF:

0.000841

AC:

128

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000509

AC:

127

AN:

249582

Hom.:

AF XY:

0.000458

AC XY:

AN XY:

135404

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000929

AC:

1358

AN:

1461730

Hom.:

Cov.:

AF XY:

0.000910

AC XY:

662

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.00116

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.000841

AC:

128

AN:

152236

Hom.:

Cov.:

AF XY:

0.000766

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00164

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00134

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000954

Hom.:

Bravo

AF:

0.000960

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00143

AC:

ExAC

AF:

0.000529

AC:

EpiCase

AF:

0.00125

EpiControl

AF:

0.00136

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:5

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MKS1 p.Asp83Gly variant was identified in multiple individuals with ciliopathies or neural tube defects as a heterozygous variant, however a second pathogenic variant was not found in these cases (Renard_2019_PMID:31139930, Davis_2011_PMID:21258341, Otto_2011_PMID:21068128). A functional study conducted on this variant suggested this variant may impact protein function (Leitch_2008_PMID:18327255). The variant was identified in dbSNP (ID: rs151023718) and ClinVar (classified as uncertain significance by Invitae, Counsyl, and three other laboratories, and as as likely pathogenic by Medical Genetics Laboratory, Kennedy Center, Juliane Marie Center, Rigshospitalet). The variant was identified in control databases in 144 of 280976 chromosomes at a frequency of 0.0005125 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 128 of 128714 chromosomes (freq: 0.000995), Other in 3 of 7152 chromosomes (freq: 0.00042), African in 6 of 24200 chromosomes (freq: 0.000248), European (Finnish) in 4 of 25036 chromosomes (freq: 0.00016), Ashkenazi Jewish in 1 of 10362 chromosomes (freq: 0.000097) and Latino in 2 of 35376 chromosomes (freq: 0.000057), but was not observed in the East Asian or South Asian populations. The p.Asp83 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The p.Asp83Gly variant occurs in the second last base of the exon; this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the loss of the canonical 5' splice site. However, this has not been confirmed by RNA analysis and is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 11, 2017	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2023	Reported in the heterozygous state in patients with nephronophthisis, Bardet-Biedl syndrome, and a developmental eye defect with no second MKS1 variant reported (Leitch et al., 2008; Otto et al., 2011; Haer-Wigman et al., 2017); Reported in the heterozygous state in a patient with Bardet-Biedl who was also heterozygous for a variant in the RPGRIP1L gene (Khanna et al., 2009); Functional studies indicate this variant has a moderate effect on protein function and is a hypomorphic variant (Leitch et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25966130, 19430481, 28224992, 21068128, 21258341, 30718709, 31139930, 18327255, 34426522, 34573333, 32483926) -
Likely pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

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

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 17, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 03, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Sep 10, 2021	- -

not specified

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 02, 2022	DNA sequence analysis of the MKS1 gene demonstrated a sequence change, c.857A>G, in exon 8 that results in an amino acid change, p.Asp286Gly. This sequence change does not appear to have been previously described in individuals with nephronophthisis, Bardet-Biedl syndrome, Leber Congenital Amaurosis and a developmental eye defect (PMID:18327255,27353947,28224992,19430481). Experimental studies indicate this variant has a moderate effect on protein function (PMID:18327255). This sequence change has been described in the gnomAD database with a frequency of 0.09% in the European subpopulation (dbSNP rs151023718). The p.Asp286Gly change affects a highly conserved amino acid residue located in a domain of the MKS1 protein that is not known to be functional. The p.Asp286Gly substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Asp286Gly change remains unknown at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 07, 2022	Variant summary: MKS1 c.857A>G (p.Asp286Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 249582 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MKS1 causing Meckel Syndrome Type 1 (0.00051 vs 0.0011), allowing no conclusion about variant significance. c.857A>G has been reported in the literature in individuals affected with Meckel Syndrome Type 1 or related disorders. These reports do not provide unequivocal conclusions about association of the variant with Meckel Syndrome Type 1. At least one publication reports experimental evidence evaluating an impact on protein function and suggested that this variant was hypomorphic (Leitch_2008). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic n=1, VUS n=8). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Meckel syndrome, type 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Bardet-Biedl syndrome 13

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 25, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 286 of the MKS1 protein (p.Asp286Gly). This variant is present in population databases (rs151023718, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with ciliopathies (PMID: 18327255, 21068128, 21258341, 28224992). ClinVar contains an entry for this variant (Variation ID: 445724). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects MKS1 function (PMID: 18327255). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

MKS1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 08, 2024

The MKS1 c.857A>G variant is predicted to result in the amino acid substitution p.Asp286Gly. This variant has previously been identified in several individuals affected with ciliopathies (see, for example, Leitch et al. 2008. PubMed ID: 18327255; Otto et al. 2010. PubMed ID: 21068128; Davis et al. 2011. PubMed ID: 21258341; Haer-Wigman et al. 2017. PubMed ID: 28224992; Table S5, Martin-Merida et al. 2019. PubMed ID: 30902645). However, a second likely causative variant was not found in MKS1 in these cases. This variant has also been reported in a patient with hereditary vison loss (Table S12, Diñeiro et al. 2020. PubMed ID: 32483926). Mutant rescue experiments in zebrafish embryos with p.Asp286Gly resulted in only partial rescue, suggesting that this variant is a hypomorph in this artificial system (Leitch et al. 2008. PubMed ID: 18327255). However, the clinical significance of this rescue experiment is unclear. Splice-site prediction programs suggest that the c.857A>G variant may interfere with normal splicing (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). This variant is reported in 0.099% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;T;.;T

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.15

T;T;T;T

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.4

M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.0

D;.;D;.

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0040

D;.;D;.

Sift4G

Uncertain

0.0070

D;D;D;D

Polyphen

0.95

P;.;.;.

Vest4

0.87

MVP

0.94

MPC

0.71

ClinPred

0.12

GERP RS

5.9

Varity_R

0.25

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.53

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.53

Position offset: 1

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