rs151023718

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_017777.4(MKS1):​c.857A>T​(p.Asp286Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D286G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MKS1
NM_017777.4 missense, splice_region

Scores

10
7
2
Splicing: ADA: 0.9999
2

Clinical Significance

Not reported in ClinVar

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-58212983-T-C is described in Lovd as [Pathogenic].
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 rank MANE Protein UniProt
MKS1NM_017777.4 linkc.857A>T p.Asp286Val missense_variant, splice_region_variant Exon 8 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.857A>T p.Asp286Val missense_variant, splice_region_variant Exon 8 of 18 1 NM_017777.4 ENSP00000376827.2 Q9NXB0-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461732
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.57
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
36
DANN
Uncertain
0.99
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
0.93
D;D;D;D
M_CAP
Pathogenic
0.29
D
MetaRNN
Pathogenic
0.87
D;D;D;D
MetaSVM
Benign
-0.44
T
MutationAssessor
Uncertain
2.4
M;.;.;.
PrimateAI
Uncertain
0.63
T
PROVEAN
Uncertain
-3.4
D;.;D;.
REVEL
Pathogenic
0.81
Sift
Uncertain
0.0020
D;.;D;.
Sift4G
Uncertain
0.0040
D;D;D;D
Polyphen
0.99
D;.;.;.
Vest4
0.80
MutPred
0.77
Gain of sheet (P = 0.0166);Gain of sheet (P = 0.0166);.;.;
MVP
0.93
MPC
0.90
ClinPred
0.97
D
GERP RS
5.9
Varity_R
0.29
gMVP
0.76

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
SpliceAI score (max)
0.97
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.97
Position offset: 2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-56290344; API