rs151023718

chr17-58212983-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

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:1 U:15
• Conservation: PhyloP100: 6.76

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 Uncertain_significance. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MKS1	NM_017777.4	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	c.857A>G	p.Asp286Gly	missense_variant, splice_region_variant	8/18	1	NM_017777.4	P1

Frequencies

GnomAD3 genomes AF: 0.000841 AC: 128 AN: 152118 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000458 AC XY: 62 AN XY: 135404

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.: 2 Cov.: 33 AF XY: 0.000910 AC XY: 662 AN XY: 727190

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.: 0 Cov.: 32 AF XY: 0.000766 AC XY: 57 AN XY: 74442

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.: 0

Bravo AF: 0.000960

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00143 AC: 12

ExAC AF: 0.000529 AC: 64

EpiCase AF: 0.00125

EpiControl AF: 0.00136

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 11, 2017	- -
Likely pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -
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) -
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. -

Bardet-Biedl syndrome 13;C3714506:Meckel syndrome, type 1;C4310705:Joubert syndrome 28 Uncertain:3

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	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 17, 2022	- -

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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -

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

Invitae

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, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 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 (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. 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	T
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	34
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	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.4	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.65	T
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	T
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

Other links and lift over

dbSNP: rs151023718; hg19: chr17-56290344;