1-186312884-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_005807.6(PRG4):c.4107C>A(p.Ala1369=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00351 in 1,612,100 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (18 hom.)
• Consequence: PRG4 NM_005807.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.416

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 1-186312884-C-A is Benign according to our data. Variant chr1-186312884-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 732422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.416 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00298 (453/152248) while in subpopulation AMR AF= 0.00713 (109/15288). AF 95% confidence interval is 0.00604. There are 3 homozygotes in gnomad4. There are 202 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRG4	NM_005807.6	c.4107C>A	p.Ala1369=	synonymous_variant	12/13	ENST00000445192.7
TPR	NM_003292.3	c.*1087G>T		3_prime_UTR_variant	51/51	ENST00000367478.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRG4	ENST00000445192.7	c.4107C>A	p.Ala1369=	synonymous_variant	12/13	5	NM_005807.6	P2
TPR	ENST00000367478.9	c.*1087G>T		3_prime_UTR_variant	51/51	1	NM_003292.3	P1

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 453 AN: 152130 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00714

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00353

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00311 AC: 782 AN: 251316 Hom.: 2 AF XY: 0.00306 AC XY: 416 AN XY: 135834

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00518

Gnomad ASJ exome AF: 0.0149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00337

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00357 AC: 5209 AN: 1459852 Hom.: 18 Cov.: 31 AF XY: 0.00351 AC XY: 2546 AN XY: 726328

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00564

Gnomad4 ASJ exome AF: 0.0131

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.000749

Gnomad4 NFE exome AF: 0.00388

Gnomad4 OTH exome AF: 0.00370

GnomAD4 genome AF: 0.00298 AC: 453 AN: 152248 Hom.: 3 Cov.: 33 AF XY: 0.00271 AC XY: 202 AN XY: 74454

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00713

Gnomad4 ASJ AF: 0.0158

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00353

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00427 Hom.: 0

Bravo AF: 0.00355

EpiCase AF: 0.00414

EpiControl AF: 0.00468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	PRG4: BP4, BP7, BS2; TPR: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
Cadd	Benign	9.2
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs80196755; hg19: chr1-186282016;