Genetic Variant MKS1:c.*414C>T (chr17-58205665-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017777.4(MKS1):c.*414C>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 0.0986 in 1,309,414 control chromosomes in the GnomAD database, including 6,616 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.083 ( 590 hom., cov: 32)

Exomes 𝑓: 0.10 ( 6026 hom. )

Consequence

MKS1
NM_017777.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.67

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]

MKS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 17-58205665-G-A is Benign according to our data. Variant chr17-58205665-G-A is described in ClinVar as [Benign]. Clinvar id is 324154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKS1	NM_017777.4 link	c.*414C>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
MKS1	ENST00000393119 link	c.*414C>T		3_prime_UTR_variant	Exon 18 of 18	1	NM_017777.4	ENSP00000376827.2		Q9NXB0-1

Frequencies

GnomAD3 genomes

AF:

0.0834

AC:

12674

AN:

152006

Hom.:

591

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0429

Gnomad AMI

AF:

0.0888

Gnomad AMR

AF:

0.0683

Gnomad ASJ

AF:

0.0877

Gnomad EAS

AF:

0.106

Gnomad SAS

AF:

0.117

Gnomad FIN

AF:

0.0963

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.105

Gnomad OTH

AF:

0.0911

GnomAD3 exomes

AF:

0.0918

AC:

13946

AN:

151976

Hom.:

697

AF XY:

0.0944

AC XY:

7706

AN XY:

81598

show subpopulations

Gnomad AFR exome

AF:

0.0410

Gnomad AMR exome

AF:

0.0517

Gnomad ASJ exome

AF:

0.0799

Gnomad EAS exome

AF:

0.115

Gnomad SAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.0930

Gnomad NFE exome

AF:

0.104

Gnomad OTH exome

AF:

0.100

GnomAD4 exome

AF:

0.101

AC:

116446

AN:

1157290

Hom.:

6026

Cov.:

AF XY:

0.101

AC XY:

57287

AN XY:

567526

show subpopulations

Gnomad4 AFR exome

AF:

0.0423

Gnomad4 AMR exome

AF:

0.0515

Gnomad4 ASJ exome

AF:

0.0810

Gnomad4 EAS exome

AF:

0.114

Gnomad4 SAS exome

AF:

0.112

Gnomad4 FIN exome

AF:

0.0935

Gnomad4 NFE exome

AF:

0.103

Gnomad4 OTH exome

AF:

0.0969

GnomAD4 genome

AF:

0.0833

AC:

12677

AN:

152124

Hom.:

590

Cov.:

AF XY:

0.0848

AC XY:

6307

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0429

Gnomad4 AMR

AF:

0.0682

Gnomad4 ASJ

AF:

0.0877

Gnomad4 EAS

AF:

0.106

Gnomad4 SAS

AF:

0.118

Gnomad4 FIN

AF:

0.0963

Gnomad4 NFE

AF:

0.105

Gnomad4 OTH

AF:

0.0906

Alfa

AF:

0.0987

Hom.:

1256

Bravo

AF:

0.0790

Asia WGS

AF:

0.0980

AC:

343

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Meckel syndrome, type 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Bardet-Biedl syndrome 13

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.36

DANN

Benign

0.46

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over