Genetic Variant NM_017777.4:c.1112_1114delTCT (chr17-58208155-GAGA-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM4_SupportingPP5_Moderate

The NM_017777.4(MKS1):c.1112_1114delTCT(p.Phe371del) variant causes a disruptive 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 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 5.08

Publications

2 publications found

Variant links:

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

MKS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

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 VariationId is 1394.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017777.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MKS1	NM_017777.4	MANE Select	c.1112_1114delTCT	p.Phe371del	disruptive_inframe_deletion	Exon 13 of 18	NP_060247.2
MKS1	NM_001321269.2		c.1112_1114delTCT	p.Phe371del	disruptive_inframe_deletion	Exon 13 of 17	NP_001308198.1
MKS1	NM_001330397.2		c.1112_1114delTCT	p.Phe371del	disruptive_inframe_deletion	Exon 13 of 16	NP_001317326.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MKS1	ENST00000393119.7	TSL:1 MANE Select	c.1112_1114delTCT	p.Phe371del	disruptive_inframe_deletion	Exon 13 of 18	ENSP00000376827.2
MKS1	ENST00000537529.7	TSL:1	c.683_685delTCT	p.Phe228del	disruptive_inframe_deletion	Exon 13 of 18	ENSP00000442096.3
MKS1	ENST00000678463.1		c.1112_1114delTCT	p.Phe371del	disruptive_inframe_deletion	Exon 13 of 17	ENSP00000502984.1

Frequencies

GnomAD3 genomes

Cov.:

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

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 13

Pathogenic:2

Sep 14, 2012

InterGenetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Apr 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.1

Mutation Taster

=45/55

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over