1-186304862-C-T

Position:

• chr1-186304862-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005807.6(PRG4):​c.538C>T​(p.Arg180Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 1,612,090 control chromosomes in the GnomAD database, including 86,999 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.29 (6891 hom., cov: 32)
  • Exomes 𝑓: 0.33 (80108 hom.)
• Consequence: PRG4 NM_005807.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:4
• Conservation: PhyloP100: 1.58

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004346609).
• BP6: Variant 1-186304862-C-T is Benign according to our data. Variant chr1-186304862-C-T is described in ClinVar as [Benign]. Clinvar id is 518309.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-186304862-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRG4	NM_005807.6	c.538C>T	p.Arg180Trp	missense_variant	6/13	ENST00000445192.7	NP_005798.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRG4	ENST00000445192.7	c.538C>T	p.Arg180Trp	missense_variant	6/13	5	NM_005807.6	ENSP00000399679	P2

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43806 AN: 151728 Hom.: 6878 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.344

Gnomad OTH AF: 0.304

GnomAD3 exomes AF: 0.311 AC: 77080 AN: 247790 Hom.: 12956 AF XY: 0.308 AC XY: 41434 AN XY: 134432

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.348

Gnomad EAS exome AF: 0.143

Gnomad SAS exome AF: 0.234

Gnomad FIN exome AF: 0.286

Gnomad NFE exome AF: 0.343

Gnomad OTH exome AF: 0.327

GnomAD4 exome AF: 0.326 AC: 475736 AN: 1460242 Hom.: 80108 Cov.: 35 AF XY: 0.323 AC XY: 234734 AN XY: 726474

Gnomad4 AFR exome AF: 0.184

Gnomad4 AMR exome AF: 0.423

Gnomad4 ASJ exome AF: 0.351

Gnomad4 EAS exome AF: 0.119

Gnomad4 SAS exome AF: 0.231

Gnomad4 FIN exome AF: 0.289

Gnomad4 NFE exome AF: 0.343

Gnomad4 OTH exome AF: 0.309

GnomAD4 genome AF: 0.289 AC: 43838 AN: 151848 Hom.: 6891 Cov.: 32 AF XY: 0.286 AC XY: 21245 AN XY: 74216

Gnomad4 AFR AF: 0.186

Gnomad4 AMR AF: 0.383

Gnomad4 ASJ AF: 0.351

Gnomad4 EAS AF: 0.145

Gnomad4 SAS AF: 0.221

Gnomad4 FIN AF: 0.290

Gnomad4 NFE AF: 0.344

Gnomad4 OTH AF: 0.309

Alfa AF: 0.336 Hom.: 21912

Bravo AF: 0.294

TwinsUK AF: 0.335 AC: 1241

ALSPAC AF: 0.332 AC: 1278

ESP6500AA AF: 0.187 AC: 822

ESP6500EA AF: 0.353 AC: 3031

ExAC AF: 0.304 AC: 36910

Asia WGS AF: 0.224 AC: 778 AN: 3472

EpiCase AF: 0.351

EpiControl AF: 0.360

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Camptodactyly-arthropathy-coxa vara-pericarditis syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.78	T;T;T
MetaRNN	Benign	0.0043	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.9	.;L;.
MutationTaster	Benign	0.97	P;P;P;P;P
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-6.0	D;D;D
REVEL	Benign	0.11
Sift	Benign	0.035	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.95, 0.97	.;P;D
Vest4		0.20, 0.38
MPC		0.11
ClinPred		0.052	T
GERP RS		4.3
Varity_R		0.17
gMVP		0.13

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: rs2273779; hg19: chr1-186273994; COSMIC: COSV66623135;