rs201845154

chr17-58214760-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017777.4(MKS1):c.496C>T(p.Arg166Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000971 in 1,606,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R166Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: MKS1 NM_017777.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6
• Conservation: PhyloP100: 3.84

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42046538).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MKS1	NM_017777.4	c.496C>T	p.Arg166Trp	missense_variant	5/18	ENST00000393119.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MKS1	ENST00000393119.7	c.496C>T	p.Arg166Trp	missense_variant	5/18	1	NM_017777.4	P1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000870

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000180 AC: 44 AN: 244194 Hom.: 0 AF XY: 0.000150 AC XY: 20 AN XY: 132960

Gnomad AFR exome AF: 0.000648

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000657

Gnomad FIN exome AF: 0.00136

Gnomad NFE exome AF: 0.0000620

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000763 AC: 111 AN: 1454432 Hom.: 0 Cov.: 30 AF XY: 0.0000829 AC XY: 60 AN XY: 723844

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.00110

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000995

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74288

Gnomad4 AFR AF: 0.000870

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000661

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000120 Hom.: 0

Bravo AF: 0.000230

ESP6500AA AF: 0.000957 AC: 4

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000240 AC: 29

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 12, 2024	Variant summary: MKS1 c.496C>T (p.Arg166Trp) 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 0.00018 in 244194 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MKS1 causing Meckel Syndrome Type 1 (0.00018 vs 0.0011), allowing no conclusion about variant significance. c.496C>T has been reported in the literature in the compound heterozygous state in at least one individual affected with Meckel Syndrome Type 1 (e.g. Tallila_2009). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 19466712). ClinVar contains an entry for this variant (Variation ID: 291155). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 03, 2017	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 08, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2022	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: 19466712) -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 166 of the MKS1 protein (p.Arg166Trp). This variant is present in population databases (rs201845154, gnomAD 0.1%). This missense change has been observed in individual(s) with Meckel syndrome (PMID: 19466712). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 291155). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MKS1 protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Meckel syndrome, type 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 24, 2020

- -

MKS1-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2023

The MKS1 c.496C>T variant is predicted to result in the amino acid substitution p.Arg166Trp. This variant has been reported in the compound heterozygous state in a fetus with suspected Meckel syndrome (Tallila et al. 2009. PubMed ID: 19466712). This variant is reported in 0.14% of alleles in individuals of European (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	Benign	0.18
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	29
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.63	D;T;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.42	T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.5	M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.4	N;D;N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.76
MVP		0.95
MPC		0.92
ClinPred		0.23	T
GERP RS		5.7
Varity_R		0.15
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.28		Position offset: -19

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201845154; hg19: chr17-56292121;