Genetic Variant PRG4:p.Gln89His (chr1-186301659-A-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005807.6(PRG4):c.267A>T(p.Gln89His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q89Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PRG4
NM_005807.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.92

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

camptodactyly-arthropathy-coxa vara-pericarditis syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Illumina, Labcorp Genetics (formerly Invitae)

PRG4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33270007).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRG4	NM_005807.6	MANE Select	c.267A>T	p.Gln89His	missense	Exon 4 of 13	NP_005798.3	Q92954-1
PRG4	NM_001127708.3		c.144A>T	p.Gln48His	missense	Exon 3 of 12	NP_001121180.2	Q92954-2
PRG4	NM_001303232.2		c.267A>T	p.Gln89His	missense	Exon 4 of 12	NP_001290161.1	Q92954-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRG4	ENST00000445192.7	TSL:5 MANE Select	c.267A>T	p.Gln89His	missense	Exon 4 of 13	ENSP00000399679.3	Q92954-1
PRG4	ENST00000367483.8	TSL:5	c.144A>T	p.Gln48His	missense	Exon 3 of 12	ENSP00000356453.4	Q92954-2
PRG4	ENST00000635041.1	TSL:5	c.267A>T	p.Gln89His	missense	Exon 4 of 12	ENSP00000489292.1	Q92954-6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461634

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111790

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.0080

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.092

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.14

M_CAP

Benign

0.027

MetaRNN

Benign

0.33

MetaSVM

Benign

-0.62

MutationAssessor

Uncertain

2.0

PhyloP100

-4.9

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.13

Sift

Benign

0.069

Sift4G

Benign

0.069

Polyphen

0.97

Vest4

0.22

MutPred

0.36

Loss of stability (P = 0.1621)

MVP

0.095

MPC

0.26

ClinPred

0.54

GERP RS

-11

Varity_R

0.041

gMVP

0.46

Mutation Taster

=86/14

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over