NM_005807.6:c.3879T>C

Variant names:

• chr1-186312260-T-C
• rs138093894
• NM_005807.6:c.3879T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005807.6(PRG4):​c.3879T>C​(p.Tyr1293Tyr) 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
• Publications: 2 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.3879T>C	p.Tyr1293Tyr	synonymous	Exon 11 of 13	NP_005798.3	Q92954-1
	TPR	NM_003292.3	MANE Select	c.*1711A>G		3_prime_UTR	Exon 51 of 51	NP_003283.2	P12270-1
	PRG4	NM_001127708.3		c.3756T>C	p.Tyr1252Tyr	synonymous	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.3879T>C	p.Tyr1293Tyr	synonymous	Exon 11 of 13	ENSP00000399679.3	Q92954-1
	TPR	ENST00000367478.9	TSL:1 MANE Select	c.*1711A>G		3_prime_UTR	Exon 51 of 51	ENSP00000356448.3	P12270-1
	PRG4	ENST00000367483.8	TSL:5	c.3756T>C	p.Tyr1252Tyr	synonymous	Exon 10 of 12	ENSP00000356453.4	Q92954-2

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

GnomAD2 exomes AF: 0.00622 AC: 1560 AN: 250730 AF XY: 0.00625

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 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

African (AFR) AF: 0.00191 AC: 64 AN: 33472

American (AMR) AF: 0.00329 AC: 147 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 270 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000661 AC: 57 AN: 86252

European-Finnish (FIN) AF: 0.0182 AC: 973 AN: 53410

Middle Eastern (MID) AF: 0.00537 AC: 31 AN: 5768

European-Non Finnish (NFE) AF: 0.00842 AC: 9357 AN: 1111882

Other (OTH) AF: 0.00696 AC: 420 AN: 60388

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

African (AFR) AF: 0.00248 AC: 103 AN: 41554

American (AMR) AF: 0.00621 AC: 95 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.0172 AC: 182 AN: 10604

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00803 AC: 546 AN: 68022

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.17
DANN	Benign	0.63
PhyloP100		-1.5
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs138093894; hg19: chr1-186281392; COSMIC: COSV104422621;