chr17-58212973-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017777.4(MKS1):c.858+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 1,612,244 control chromosomes in the GnomAD database, including 168,926 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 23281 hom., cov: 31)

Exomes 𝑓: 0.44 ( 145645 hom. )

Consequence

MKS1
NM_017777.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -1.77

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

Meckel syndrome, type 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
Bardet-Biedl syndrome 13
Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
Joubert syndrome 28
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Joubert syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Joubert syndrome with ocular defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Meckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MKS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 17-58212973-T-C is Benign according to our data. Variant chr17-58212973-T-C is described in ClinVar as Benign. ClinVar VariationId is 126274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.784 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKS1	NM_017777.4 link	c.858+9A>G		intron_variant	Intron 8 of 17	ENST00000393119.7	NP_060247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKS1	ENST00000393119.7 link	c.858+9A>G		intron_variant	Intron 8 of 17	1	NM_017777.4	ENSP00000376827.2

Frequencies

GnomAD3 genomes

AF:

0.525

AC:

79717

AN:

151828

Hom.:

23227

Cov.:

show subpopulations

Gnomad AFR

AF:

0.791

Gnomad AMI

AF:

0.469

Gnomad AMR

AF:

0.343

Gnomad ASJ

AF:

0.458

Gnomad EAS

AF:

0.201

Gnomad SAS

AF:

0.428

Gnomad FIN

AF:

0.512

Gnomad MID

AF:

0.456

Gnomad NFE

AF:

0.443

Gnomad OTH

AF:

0.491

GnomAD2 exomes

AF:

0.434

AC:

108173

AN:

249504

AF XY:

0.434

show subpopulations

Gnomad AFR exome

AF:

0.803

Gnomad AMR exome

AF:

0.277

Gnomad ASJ exome

AF:

0.454

Gnomad EAS exome

AF:

0.208

Gnomad FIN exome

AF:

0.526

Gnomad NFE exome

AF:

0.446

Gnomad OTH exome

AF:

0.427

GnomAD4 exome

AF:

0.438

AC:

640240

AN:

1460298

Hom.:

145645

Cov.:

AF XY:

0.438

AC XY:

318073

AN XY:

726594

show subpopulations

African (AFR)

AF:

0.812

AC:

27173

AN:

33446

American (AMR)

AF:

0.288

AC:

12864

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.457

AC:

11933

AN:

26124

East Asian (EAS)

AF:

0.203

AC:

8068

AN:

39686

South Asian (SAS)

AF:

0.445

AC:

38361

AN:

86228

European-Finnish (FIN)

AF:

0.519

AC:

27729

AN:

53386

Middle Eastern (MID)

AF:

0.410

AC:

2363

AN:

5768

European-Non Finnish (NFE)

AF:

0.437

AC:

485112

AN:

1110606

Other (OTH)

AF:

0.441

AC:

26637

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

18295

36589

54884

73178

91473

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14562

29124

43686

58248

72810

<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:

0.525

AC:

79832

AN:

151946

Hom.:

23281

Cov.:

AF XY:

0.522

AC XY:

38786

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.792

AC:

32796

AN:

41434

American (AMR)

AF:

0.343

AC:

5239

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.458

AC:

1589

AN:

3470

East Asian (EAS)

AF:

0.201

AC:

1037

AN:

5156

South Asian (SAS)

AF:

0.429

AC:

2065

AN:

4818

European-Finnish (FIN)

AF:

0.512

AC:

5398

AN:

10546

Middle Eastern (MID)

AF:

0.452

AC:

133

AN:

294

European-Non Finnish (NFE)

AF:

0.443

AC:

30116

AN:

67924

Other (OTH)

AF:

0.489

AC:

1033

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1723

3445

5168

6890

8613

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

670

1340

2010

2680

3350

<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:

0.457

Hom.:

35777

Bravo

AF:

0.523

Asia WGS

AF:

0.344

AC:

1197

AN:

3478

EpiCase

AF:

0.427

EpiControl

AF:

0.429

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Meckel syndrome, type 1

Benign:2

Jan 12, 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.

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Bardet-Biedl syndrome 13

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Joubert syndrome 28

Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Meckel-Gruber syndrome;C0431399:Joubert syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.031

(source)

DANN

Benign

0.19

PhyloP100

-1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over