NM_005807.6:c.3905_3909delGTCGC

Variant names:

• chr1-186312284-ACGTCG-A
• NM_005807.6:c.3905_3909delGTCGC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005807.6(PRG4):​c.3905_3909delGTCGC​(p.Arg1302LeufsTer2) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRG4 NM_005807.6 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.01
• Publications: 0 publications found

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]

TPR (HGNC:12017): (translocated promoter region, nuclear basket protein) This gene encodes a large coiled-coil protein that forms intranuclear filaments attached to the inner surface of nuclear pore complexes (NPCs). The protein directly interacts with several components of the NPC. It is required for the nuclear export of mRNAs and some proteins. Oncogenic fusions of the 5' end of this gene with several different kinase genes occur in some neoplasias. [provided by RefSeq, Jul 2008]

TPR Gene-Disease associations (from GenCC):

• intellectual developmental disorder, autosomal recessive 79

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-186312284-ACGTCG-A is Pathogenic according to our data. Variant chr1-186312284-ACGTCG-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3362579.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005807.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRG4	NM_005807.6	MANE Select	c.3905_3909delGTCGC	p.Arg1302LeufsTer2	frameshift	Exon 11 of 13	NP_005798.3	Q92954-1
	TPR	NM_003292.3	MANE Select	c.*1682_*1686delCGACG		3_prime_UTR	Exon 51 of 51	NP_003283.2	P12270-1
	PRG4	NM_001127708.3		c.3782_3786delGTCGC	p.Arg1261LeufsTer2	frameshift	Exon 10 of 12	NP_001121180.2	Q92954-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRG4	ENST00000445192.7	TSL:5 MANE Select	c.3905_3909delGTCGC	p.Arg1302LeufsTer2	frameshift	Exon 11 of 13	ENSP00000399679.3	Q92954-1
	TPR	ENST00000367478.9	TSL:1 MANE Select	c.*1682_*1686delCGACG		3_prime_UTR	Exon 51 of 51	ENSP00000356448.3	P12270-1
	PRG4	ENST00000367483.8	TSL:5	c.3782_3786delGTCGC	p.Arg1261LeufsTer2	frameshift	Exon 10 of 12	ENSP00000356453.4	Q92954-2

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

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Camptodactyly-arthropathy-coxa vara-pericarditis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.0
Mutation Taster		=2/198	disease causing (fs/PTC)

Splicing

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

Other links and lift over

hg19: chr1-186281416;