1-186312878-C-G

Variant names:

• chr1-186312878-C-G
• rs1388040598
• NM_005807.6:c.4101C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_005807.6(PRG4):​c.4101C>G​(p.Tyr1367*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRG4 NM_005807.6 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.24
• Publications: 1 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: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.027 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-186312878-C-G is Pathogenic according to our data. Variant chr1-186312878-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 684667.Status of the report is no_assertion_criteria_provided, 0 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.4101C>G	p.Tyr1367*	stop_gained	Exon 12 of 13	NP_005798.3	Q92954-1
	TPR	NM_003292.3	MANE Select	c.*1093G>C		3_prime_UTR	Exon 51 of 51	NP_003283.2	P12270-1
	PRG4	NM_001127708.3		c.3978C>G	p.Tyr1326*	stop_gained	Exon 11 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.4101C>G	p.Tyr1367*	stop_gained	Exon 12 of 13	ENSP00000399679.3	Q92954-1
	TPR	ENST00000367478.9	TSL:1 MANE Select	c.*1093G>C		3_prime_UTR	Exon 51 of 51	ENSP00000356448.3	P12270-1
	PRG4	ENST00000367483.8	TSL:5	c.3978C>G	p.Tyr1326*	stop_gained	Exon 11 of 12	ENSP00000356453.4	Q92954-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		1.2
Vest4		0.57
GERP RS		2.9
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1388040598; hg19: chr1-186282010;