rs372527189

Positions:

• chr17-58214729-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017777.4(MKS1):​c.515+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000428 in 1,603,268 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (3 hom.)
• Consequence: MKS1 NM_017777.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -0.382

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-58214729-G-A is Benign according to our data. Variant chr17-58214729-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260885.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000432 (627/1451030) while in subpopulation MID AF= 0.0118 (68/5766). AF 95% confidence interval is 0.00954. There are 3 homozygotes in gnomad4_exome. There are 328 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MKS1	NM_017777.4	c.515+12C>T		intron_variant		ENST00000393119.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MKS1	ENST00000393119.7	c.515+12C>T		intron_variant		1	NM_017777.4	P1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000641 AC: 154 AN: 240228 Hom.: 0 AF XY: 0.000642 AC XY: 84 AN XY: 130852

Gnomad AFR exome AF: 0.0000658

Gnomad AMR exome AF: 0.00198

Gnomad ASJ exome AF: 0.000599

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000433

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000449

Gnomad OTH exome AF: 0.00268

GnomAD4 exome AF: 0.000432 AC: 627 AN: 1451030 Hom.: 3 Cov.: 30 AF XY: 0.000454 AC XY: 328 AN XY: 722026

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.00193

Gnomad4 ASJ exome AF: 0.000498

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000373

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000304

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74430

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000726 Hom.: 0

Bravo AF: 0.000484

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Meckel syndrome, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Bardet-Biedl syndrome 13 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.9
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs372527189; hg19: chr17-56292090;