17-58205665-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -3.67

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]

ACMG classification

Verdict is Benign. Variant got -14 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_single_submitter, 1 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/exons	MANE	UniProt
MKS1	NM_017777.4	c.*414C>T		3_prime_UTR_variant	18/18	ENST00000393119.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MKS1	ENST00000393119.7	c.*414C>T		3_prime_UTR_variant	18/18	1	NM_017777.4	P1

Frequencies

GnomAD3 genomes AF: 0.0834 AC: 12674 AN: 152006 Hom.: 591 Cov.: 32

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

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.: 31 AF XY: 0.101 AC XY: 57287 AN XY: 567526

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.: 32 AF XY: 0.0848 AC XY: 6307 AN XY: 74350

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:2

Revision: criteria provided, single submitter

Submissions by phenotype

Meckel syndrome, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

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

Other links and lift over

dbSNP: rs2302313; hg19: chr17-56283026; COSMIC: COSV56594743; COSMIC: COSV56594743;