NM_017777.4:c.191-44G>A

Variant names:

• chr17-58216780-C-T
• rs73329636
• NM_017777.4:c.191-44G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017777.4(MKS1):​c.191-44G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0336 in 1,584,240 control chromosomes in the GnomAD database, including 1,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (556 hom., cov: 32)
  • Exomes 𝑓: 0.030 (1017 hom.)
• Consequence: MKS1 NM_017777.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.506

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-58216780-C-T is Benign according to our data. Variant chr17-58216780-C-T is described in ClinVar as [Benign]. Clinvar id is 126273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKS1	NM_017777.4	c.191-44G>A		intron_variant	Intron 2 of 17	ENST00000393119.7	NP_060247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKS1	ENST00000393119.7	c.191-44G>A		intron_variant	Intron 2 of 17	1	NM_017777.4	ENSP00000376827.2

Frequencies

GnomAD3 genomes AF: 0.0631 AC: 9602 AN: 152130 Hom.: 554 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0367

Gnomad ASJ AF: 0.0669

Gnomad EAS AF: 0.00771

Gnomad SAS AF: 0.0225

Gnomad FIN AF: 0.0295

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0277

Gnomad OTH AF: 0.0645

GnomAD3 exomes AF: 0.0373 AC: 9230 AN: 247654 Hom.: 283 AF XY: 0.0356 AC XY: 4776 AN XY: 134284

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.0265

Gnomad ASJ exome AF: 0.0723

Gnomad EAS exome AF: 0.00625

Gnomad SAS exome AF: 0.0292

Gnomad FIN exome AF: 0.0277

Gnomad NFE exome AF: 0.0295

Gnomad OTH exome AF: 0.0461

GnomAD4 exome AF: 0.0305 AC: 43607 AN: 1431992 Hom.: 1017 Cov.: 26 AF XY: 0.0302 AC XY: 21602 AN XY: 714202

Gnomad4 AFR exome AF: 0.159

Gnomad4 AMR exome AF: 0.0291

Gnomad4 ASJ exome AF: 0.0700

Gnomad4 EAS exome AF: 0.0128

Gnomad4 SAS exome AF: 0.0291

Gnomad4 FIN exome AF: 0.0303

Gnomad4 NFE exome AF: 0.0257

Gnomad4 OTH exome AF: 0.0390

GnomAD4 genome AF: 0.0631 AC: 9609 AN: 152248 Hom.: 556 Cov.: 32 AF XY: 0.0622 AC XY: 4634 AN XY: 74442

Gnomad4 AFR AF: 0.152

Gnomad4 AMR AF: 0.0367

Gnomad4 ASJ AF: 0.0669

Gnomad4 EAS AF: 0.00772

Gnomad4 SAS AF: 0.0223

Gnomad4 FIN AF: 0.0295

Gnomad4 NFE AF: 0.0277

Gnomad4 OTH AF: 0.0639

Alfa AF: 0.0496 Hom.: 59

Bravo AF: 0.0685

Asia WGS AF: 0.0200 AC: 70 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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. -

not provided Benign:2

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Bardet-Biedl syndrome 13 Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 28 Benign:1

Jun 10, 2021

Genome-Nilou Lab

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	-0.84
CADD	Benign	11
DANN	Benign	0.70

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: rs73329636; hg19: chr17-56294141;