NM_005807.6:c.659A>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005807.6(PRG4):c.659A>C(p.Asp220Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,612,992 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0068 ( 13 hom., cov: 32)

Exomes 𝑓: 0.00096 ( 20 hom. )

Consequence

PRG4
NM_005807.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.520

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006234437).

BP6

Variant 1-186306378-A-C is Benign according to our data. Variant chr1-186306378-A-C is described in ClinVar as [Benign]. Clinvar id is 767737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00681 (1037/152242) while in subpopulation AFR AF= 0.0224 (931/41518). AF 95% confidence interval is 0.0212. There are 13 homozygotes in gnomad4. There are 497 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRG4	NM_005807.6 link	c.659A>C	p.Asp220Ala	missense_variant	Exon 7 of 13	ENST00000445192.7	NP_005798.3	Q92954-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRG4	ENST00000445192.7 link	c.659A>C	p.Asp220Ala	missense_variant	Exon 7 of 13	5	NM_005807.6	ENSP00000399679.3		Q92954-1

Frequencies

GnomAD3 genomes

AF:

0.00678

AC:

1031

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00367

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00216

AC:

542

AN:

250798

Hom.:

AF XY:

0.00161

AC XY:

218

AN XY:

135508

show subpopulations

Gnomad AFR exome

AF:

0.0239

Gnomad AMR exome

AF:

0.00253

Gnomad ASJ exome

AF:

0.000299

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000423

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.000959

AC:

1401

AN:

1460750

Hom.:

Cov.:

AF XY:

0.000827

AC XY:

601

AN XY:

726630

show subpopulations

Gnomad4 AFR exome

AF:

0.0231

Gnomad4 AMR exome

AF:

0.00269

Gnomad4 ASJ exome

AF:

0.000460

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000163

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000265

Gnomad4 OTH exome

AF:

0.00275

GnomAD4 genome

AF:

0.00681

AC:

1037

AN:

152242

Hom.:

Cov.:

AF XY:

0.00668

AC XY:

497

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0224

Gnomad4 AMR

AF:

0.00373

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00184

Hom.:

Bravo

AF:

0.00763

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0193

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00241

AC:

292

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 08, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.10

T;T;.;T;.;.

Eigen

Benign

-0.000040

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.71

T;T;T;T;T;T

MetaRNN

Benign

0.0062

T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.2

.;.;.;M;.;.

PrimateAI

Benign

0.32

PROVEAN

Pathogenic

-6.1

D;D;.;D;D;D

REVEL

Benign

0.086

Sift

Uncertain

0.013

D;D;.;D;D;D

Sift4G

Uncertain

0.013

D;D;T;D;D;T

Polyphen

0.89, 0.99

.;.;.;P;D;D

Vest4

0.29, 0.27, 0.31, 0.23

MVP

0.17

MPC

0.27

ClinPred

0.063

GERP RS

4.0

Varity_R

0.16

gMVP

0.18

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

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