rs587777804

Positions:

• chr17-58208155-GAGA-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP5_Moderate

The NM_017777.4(MKS1):​c.1112_1114del​(p.Phe371del) variant causes a inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. F371F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MKS1 NM_017777.4 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.08

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain C2 B9-type (size 128) in uniprot entity MKS1_HUMAN there are 16 pathogenic changes around while only 4 benign (80%) in NM_017777.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_017777.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 17-58208155-GAGA-G is Pathogenic according to our data. Variant chr17-58208155-GAGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 1394.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MKS1	NM_017777.4	c.1112_1114del	p.Phe371del	inframe_deletion	13/18	ENST00000393119.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MKS1	ENST00000393119.7	c.1112_1114del	p.Phe371del	inframe_deletion	13/18	1	NM_017777.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Bardet-Biedl syndrome 13 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	InterGenetics	Sep 14, 2012	The c.1112_1114delTCT (p.Phe371del) variant in MKS1 was found in compound heterozygous state in a patient of Turkish descent with Bardet-Biedl syndrome-13 (BBS13; 615990) by Leitch et al. (2008), in compound heterozygosity with the MKS1 c.1476C>G (p.Cys492Trp) variant. The variant is not present in 1000 control Greek chromosomes. In summary, the p.Phe371del variant meets our criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs587777804; hg19: chr17-56285516;