Variant 1-186312769-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005807.6(PRG4):c.3992G>A(p.Gly1331Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,550 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PRG4
NM_005807.6 missense, splice_region

Scores

Splicing: ADA: 0.01708

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.42

Variant links:

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]

PRG4 links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRG4	NM_005807.6 linkuse as main transcript	c.3992G>A	p.Gly1331Asp	missense_variant, splice_region_variant	12/13	ENST00000445192.7	NP_005798.3	Q92954-1
TPR	NM_003292.3 linkuse as main transcript	c.*1202C>T		3_prime_UTR_variant	51/51	ENST00000367478.9	NP_003283.2	P12270-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRG4	ENST00000445192.7 linkuse as main transcript	c.3992G>A	p.Gly1331Asp	missense_variant, splice_region_variant	12/13	5	NM_005807.6	ENSP00000399679.3		Q92954-1
TPR	ENST00000367478 linkuse as main transcript	c.*1202C>T		3_prime_UTR_variant	51/51	1	NM_003292.3	ENSP00000356448.3		P12270-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251224

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460550

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726650

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2024

The c.3992G>A (p.G1331D) alteration is located in exon 12 (coding exon 11) of the PRG4 gene. This alteration results from a G to A substitution at nucleotide position 3992, causing the glycine (G) at amino acid position 1331 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.35

.;T;.;.

Eigen

Benign

0.015

Eigen_PC

Benign

-0.037

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.70

T;T;T;T

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.45

T;T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.9

.;L;.;.

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-5.9

.;D;D;D

REVEL

Benign

0.14

Sift

Uncertain

0.0020

.;D;D;D

Sift4G

Benign

0.061

T;T;T;T

Polyphen

0.98, 0.93, 0.85

.;D;P;P

Vest4

0.42

MutPred

0.40

.;Gain of loop (P = 0.1069);.;.;

MVP

0.24

MPC

0.042

ClinPred

0.87

GERP RS

2.6

Varity_R

0.058

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.017

dbscSNV1_RF

Benign

0.22

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over