17-58205757-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_017777.4(MKS1):​c.*322G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00736 in 1,398,458 control chromosomes in the GnomAD database, including 62 homozygotes. 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 0.0056 ( 8 hom., cov: 32)
Exomes 𝑓: 0.0076 ( 54 hom. )

Consequence

MKS1
NM_017777.4 3_prime_UTR

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: -0.160
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_benign. Variant got -4 ACMG points.

BS2
High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MKS1NM_017777.4 linkc.*322G>T 3_prime_UTR_variant Exon 18 of 18 ENST00000393119.7 NP_060247.2 Q9NXB0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MKS1ENST00000393119 linkc.*322G>T 3_prime_UTR_variant Exon 18 of 18 1 NM_017777.4 ENSP00000376827.2 Q9NXB0-1

Frequencies

GnomAD3 genomes
AF:
0.00562
AC:
855
AN:
152124
Hom.:
8
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00123
Gnomad AMI
AF:
0.0450
Gnomad AMR
AF:
0.00340
Gnomad ASJ
AF:
0.00951
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00642
Gnomad FIN
AF:
0.00942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00779
Gnomad OTH
AF:
0.00766
GnomAD4 exome
AF:
0.00757
AC:
9435
AN:
1246216
Hom.:
54
Cov.:
31
AF XY:
0.00751
AC XY:
4595
AN XY:
611864
show subpopulations
Gnomad4 AFR exome
AF:
0.000901
Gnomad4 AMR exome
AF:
0.00218
Gnomad4 ASJ exome
AF:
0.00936
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00747
Gnomad4 FIN exome
AF:
0.00905
Gnomad4 NFE exome
AF:
0.00800
Gnomad4 OTH exome
AF:
0.00765
GnomAD4 genome
AF:
0.00562
AC:
856
AN:
152242
Hom.:
8
Cov.:
32
AF XY:
0.00557
AC XY:
415
AN XY:
74440
show subpopulations
Gnomad4 AFR
AF:
0.00123
Gnomad4 AMR
AF:
0.00340
Gnomad4 ASJ
AF:
0.00951
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00663
Gnomad4 FIN
AF:
0.00942
Gnomad4 NFE
AF:
0.00779
Gnomad4 OTH
AF:
0.00758
Alfa
AF:
0.00107
Hom.:
0
Bravo
AF:
0.00527
Asia WGS
AF:
0.00289
AC:
12
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

MKS1: BS2 -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Meckel syndrome, type 1 Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Bardet-Biedl syndrome 13 Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.80
CADD
Benign
17
DANN
Benign
0.78
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.24
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.24
Position offset: -13

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: rs185405908; hg19: chr17-56283118; API