rs200340896

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001321268.2(MKS1):​c.-313C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000818 in 1,613,964 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).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

MKS1
NM_001321268.2 5_prime_UTR_premature_start_codon_gain

Scores

1
4
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 0.945
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.12992534).
BP6
Variant 17-58216728-G-A is Benign according to our data. Variant chr17-58216728-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 461763.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MKS1NM_017777.4 linkc.199C>T p.Arg67Cys missense_variant Exon 3 of 18 ENST00000393119.7 NP_060247.2 Q9NXB0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MKS1ENST00000393119.7 linkc.199C>T p.Arg67Cys missense_variant Exon 3 of 18 1 NM_017777.4 ENSP00000376827.2 Q9NXB0-1

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
152132
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000589
Gnomad ASJ
AF:
0.000866
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.000478
GnomAD2 exomes
AF:
0.000120
AC:
30
AN:
249504
AF XY:
0.000133
show subpopulations
Gnomad AFR exome
AF:
0.0000646
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.000794
Gnomad EAS exome
AF:
0.000278
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000530
Gnomad OTH exome
AF:
0.000495
GnomAD4 exome
AF:
0.0000759
AC:
111
AN:
1461832
Hom.:
0
Cov.:
32
AF XY:
0.0000756
AC XY:
55
AN XY:
727210
show subpopulations
Gnomad4 AFR exome
AF:
0.00
AC:
0
AN:
33478
Gnomad4 AMR exome
AF:
0.000157
AC:
7
AN:
44718
Gnomad4 ASJ exome
AF:
0.000612
AC:
16
AN:
26136
Gnomad4 EAS exome
AF:
0.000176
AC:
7
AN:
39700
Gnomad4 SAS exome
AF:
0.0000348
AC:
3
AN:
86238
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
53414
Gnomad4 NFE exome
AF:
0.0000549
AC:
61
AN:
1111986
Gnomad4 Remaining exome
AF:
0.000265
AC:
16
AN:
60394
Heterozygous variant carriers
0
6
12
19
25
31
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000138
AC:
21
AN:
152132
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74314
show subpopulations
Gnomad4 AFR
AF:
0.0000724
AC:
0.0000723798
AN:
0.0000723798
Gnomad4 AMR
AF:
0.000589
AC:
0.000589468
AN:
0.000589468
Gnomad4 ASJ
AF:
0.000866
AC:
0.000865551
AN:
0.000865551
Gnomad4 EAS
AF:
0.000192
AC:
0.000192456
AN:
0.000192456
Gnomad4 SAS
AF:
0.000207
AC:
0.000207297
AN:
0.000207297
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.0000441
AC:
0.0000441138
AN:
0.0000441138
Gnomad4 OTH
AF:
0.000478
AC:
0.000478011
AN:
0.000478011
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000809
Hom.:
0
Bravo
AF:
0.000147
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000121
AC:
1
ExAC
AF:
0.0000910
AC:
11
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Aug 22, 2017
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Sep 15, 2022
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Meckel syndrome, type 1 Uncertain:1
Jan 17, 2020
Natera, Inc.
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

MKS1-related disorder Uncertain:1
Mar 13, 2024
PreventionGenetics, part of Exact Sciences
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

The MKS1 c.199C>T variant is predicted to result in the amino acid substitution p.Arg67Cys. This variant, along with missense variants in other genes, has been reported with uncertain significance in an individual with congenital contractural arachnodactyly in whom a likely pathogenic variant in FBN2 was also found (Table 2, Li AL et al. 2023. PubMed ID: 36936417). This variant is reported in 0.087% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. 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:Joubert syndrome Benign:1
Dec 30, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.094
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.17
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.23
T;T;.
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Benign
0.68
D
LIST_S2
Uncertain
0.91
D;D;D
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.13
T;T;T
MetaSVM
Benign
-0.54
T
MutationAssessor
Benign
1.9
L;.;.
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-1.2
N;.;N
REVEL
Benign
0.20
Sift
Benign
0.036
D;.;D
Sift4G
Uncertain
0.015
D;D;D
Polyphen
0.98
D;.;.
Vest4
0.30
MVP
0.80
MPC
0.34
ClinPred
0.050
T
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.10
gMVP
0.31
Mutation Taster
=88/12
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200340896; hg19: chr17-56294089; COSMIC: COSV58303043; COSMIC: COSV58303043; API