17-58205607-G-C

Variant names:

• chr17-58205607-G-C
• rs17174788
• NM_017777.4:c.*472C>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_017777.4(MKS1):​c.*472C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0581 in 1,306,094 control chromosomes in the GnomAD database, including 2,450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (214 hom., cov: 32)
  • Exomes 𝑓: 0.060 (2236 hom.)
• Consequence: MKS1 NM_017777.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.69
• Publications: 7 publications found

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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.031).
• BP6: Variant 17-58205607-G-C is Benign according to our data. Variant chr17-58205607-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 892306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKS1	NM_017777.4	c.*472C>G		3_prime_UTR_variant	Exon 18 of 18	ENST00000393119.7	NP_060247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKS1	ENST00000393119.7	c.*472C>G		3_prime_UTR_variant	Exon 18 of 18	1	NM_017777.4	ENSP00000376827.2

Frequencies

GnomAD3 genomes AF: 0.0471 AC: 7172 AN: 152126 Hom.: 214 Cov.: 32

Gnomad AFR AF: 0.0254

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.0519

Gnomad ASJ AF: 0.0757

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.0275

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0652

Gnomad OTH AF: 0.0583

GnomAD2 exomes AF: 0.0434 AC: 6593 AN: 151742 AF XY: 0.0430

Gnomad AFR exome AF: 0.0260

Gnomad AMR exome AF: 0.0360

Gnomad ASJ exome AF: 0.0708

Gnomad EAS exome AF: 0.000185

Gnomad FIN exome AF: 0.0264

Gnomad NFE exome AF: 0.0679

Gnomad OTH exome AF: 0.0570

GnomAD4 exome AF: 0.0596 AC: 68775 AN: 1153850 Hom.: 2236 Cov.: 30 AF XY: 0.0584 AC XY: 33024 AN XY: 565792

African (AFR) AF: 0.0235 AC: 575 AN: 24492

American (AMR) AF: 0.0363 AC: 1027 AN: 28294

Ashkenazi Jewish (ASJ) AF: 0.0708 AC: 1134 AN: 16026

East Asian (EAS) AF: 0.0000774 AC: 1 AN: 12926

South Asian (SAS) AF: 0.0146 AC: 1109 AN: 76218

European-Finnish (FIN) AF: 0.0260 AC: 712 AN: 27408

Middle Eastern (MID) AF: 0.112 AC: 495 AN: 4406

European-Non Finnish (NFE) AF: 0.0665 AC: 61366 AN: 922304

Other (OTH) AF: 0.0564 AC: 2356 AN: 41776

GnomAD4 genome AF: 0.0471 AC: 7168 AN: 152244 Hom.: 214 Cov.: 32 AF XY: 0.0438 AC XY: 3259 AN XY: 74430

African (AFR) AF: 0.0254 AC: 1053 AN: 41532

American (AMR) AF: 0.0518 AC: 793 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0757 AC: 263 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0114 AC: 55 AN: 4824

European-Finnish (FIN) AF: 0.0275 AC: 292 AN: 10604

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0652 AC: 4431 AN: 68004

Other (OTH) AF: 0.0572 AC: 121 AN: 2116

Alfa AF: 0.0507 Hom.: 91

Bravo AF: 0.0489

Asia WGS AF: 0.00895 AC: 32 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Meckel syndrome, type 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely 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	-0.79
CADD	Benign	0.066
DANN	Benign	0.93
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17174788; hg19: chr17-56282968;