1-186312260-T-C

Position:

• chr1-186312260-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005807.6(PRG4):​c.3879T>C​(p.Tyr1293=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00761 in 1,613,984 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (57 hom.)
• Consequence: PRG4 NM_005807.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.53

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 1-186312260-T-C is Benign according to our data. Variant chr1-186312260-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 781667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00638 (971/152280) while in subpopulation NFE AF= 0.00803 (546/68022). AF 95% confidence interval is 0.00747. There are 6 homozygotes in gnomad4. There are 510 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRG4	NM_005807.6	c.3879T>C	p.Tyr1293=	synonymous_variant	11/13	ENST00000445192.7	NP_005798.3
TPR	NM_003292.3	c.*1711A>G		3_prime_UTR_variant	51/51	ENST00000367478.9	NP_003283.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRG4	ENST00000445192.7	c.3879T>C	p.Tyr1293=	synonymous_variant	11/13	5	NM_005807.6	ENSP00000399679	P2
TPR	ENST00000367478.9	c.*1711A>G		3_prime_UTR_variant	51/51	1	NM_003292.3	ENSP00000356448	P1

Frequencies

GnomAD3 genomes AF: 0.00638 AC: 971 AN: 152162 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0172

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00803

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00622 AC: 1560 AN: 250730 Hom.: 6 AF XY: 0.00625 AC XY: 847 AN XY: 135618

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.0171

Gnomad NFE exome AF: 0.00790

Gnomad OTH exome AF: 0.00848

GnomAD4 exome AF: 0.00774 AC: 11319 AN: 1461704 Hom.: 57 Cov.: 31 AF XY: 0.00761 AC XY: 5535 AN XY: 727160

Gnomad4 AFR exome AF: 0.00191

Gnomad4 AMR exome AF: 0.00329

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000661

Gnomad4 FIN exome AF: 0.0182

Gnomad4 NFE exome AF: 0.00842

Gnomad4 OTH exome AF: 0.00696

GnomAD4 genome AF: 0.00638 AC: 971 AN: 152280 Hom.: 6 Cov.: 32 AF XY: 0.00685 AC XY: 510 AN XY: 74468

Gnomad4 AFR AF: 0.00248

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0172

Gnomad4 NFE AF: 0.00803

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00760 Hom.: 3

Bravo AF: 0.00532

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00944

EpiControl AF: 0.00865

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	PRG4: BP4, BP7, BS2; TPR: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.17
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs138093894; hg19: chr1-186281392; COSMIC: COSV104422621; COSMIC: COSV104422621;