1-186296896-C-CATTT

Variant names:

• chr1-186296896-C-CATTT
• NM_005807.6:c.23_26dupTTTA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_005807.6(PRG4):​c.23_26dupTTTA​(p.Leu11ProfsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRG4 NM_005807.6 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -1.32

Genes affected

PRG4 (HGNC:9364): (proteoglycan 4) The protein encoded by this gene is a large proteoglycan that is synthesized by chondrocytes located at the surface of articular cartilage and by some synovial lining cells. This protein contains both chondroitin sulfate and keratan sulfate glycosaminoglycans. It functions as a boundary lubricant at the cartilage surface and contributes to the elastic absorption and energy dissipation of synovial fluid. Mutations in this gene result in camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 19 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-186296896-C-CATTT is Pathogenic according to our data. Variant chr1-186296896-C-CATTT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3062118.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRG4	NM_005807.6	c.23_26dupTTTA	p.Leu11ProfsTer31	frameshift_variant	Exon 2 of 13	ENST00000445192.7	NP_005798.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRG4	ENST00000445192.7	c.23_26dupTTTA	p.Leu11ProfsTer31	frameshift_variant	Exon 2 of 13	5	NM_005807.6	ENSP00000399679.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Camptodactyly-arthropathy-coxa vara-pericarditis syndrome Pathogenic:1

Dec 06, 2019

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PRG4 c.23_26dupTTTA p.(Leu11ProfsTer31) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. To our knowledge, this variant has not been reported in the peer-reviewed literature. This variant is not observed in version 2.1.1 or version 4.0.0 of the Genome Aggregation Database. Based on the evidence, the c.23_26dupTTTA p.(Leu11ProfsTer31) variant is classified as likely pathogenic for camptodactyly-arthropathy-coxa vara-pericarditis syndrome. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-186266028;