1-186306432-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005807.6(PRG4):c.713C>T(p.Thr238Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0447 in 1,613,458 control chromosomes in the GnomAD database, including 1,836 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.036 (119 hom., cov: 32)
  • Exomes 𝑓: 0.046 (1717 hom.)
• Consequence: PRG4 NM_005807.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.05

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=0.0022449493).
• BP6: Variant 1-186306432-C-T is Benign according to our data. Variant chr1-186306432-C-T is described in ClinVar as [Benign]. Clinvar id is 3037150.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-186306432-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0361 (5498/152152) while in subpopulation NFE AF= 0.0485 (3296/67996). AF 95% confidence interval is 0.0471. There are 119 homozygotes in gnomad4. There are 2696 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 119 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRG4	NM_005807.6	c.713C>T	p.Thr238Met	missense_variant	7/13	ENST00000445192.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRG4	ENST00000445192.7	c.713C>T	p.Thr238Met	missense_variant	7/13	5	NM_005807.6	P2

Frequencies

GnomAD3 genomes AF: 0.0361 AC: 5496 AN: 152034 Hom.: 119 Cov.: 32

Gnomad AFR AF: 0.0183

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0433

Gnomad FIN AF: 0.0740

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0485

Gnomad OTH AF: 0.0278

GnomAD3 exomes AF: 0.0375 AC: 9434 AN: 251314 Hom.: 241 AF XY: 0.0392 AC XY: 5329 AN XY: 135818

Gnomad AFR exome AF: 0.0190

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0158

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0454

Gnomad FIN exome AF: 0.0728

Gnomad NFE exome AF: 0.0476

Gnomad OTH exome AF: 0.0346

GnomAD4 exome AF: 0.0456 AC: 66572 AN: 1461306 Hom.: 1717 Cov.: 32 AF XY: 0.0458 AC XY: 33317 AN XY: 726980

Gnomad4 AFR exome AF: 0.0174

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.0154

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0448

Gnomad4 FIN exome AF: 0.0720

Gnomad4 NFE exome AF: 0.0494

Gnomad4 OTH exome AF: 0.0392

GnomAD4 genome AF: 0.0361 AC: 5498 AN: 152152 Hom.: 119 Cov.: 32 AF XY: 0.0362 AC XY: 2696 AN XY: 74396

Gnomad4 AFR AF: 0.0183

Gnomad4 AMR AF: 0.0150

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.0435

Gnomad4 FIN AF: 0.0740

Gnomad4 NFE AF: 0.0485

Gnomad4 OTH AF: 0.0275

Alfa AF: 0.0421 Hom.: 388

Bravo AF: 0.0305

TwinsUK AF: 0.0464 AC: 172

ALSPAC AF: 0.0566 AC: 218

ESP6500AA AF: 0.0211 AC: 93

ESP6500EA AF: 0.0451 AC: 388

ExAC AF: 0.0381 AC: 4624

Asia WGS AF: 0.0200 AC: 70 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PRG4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 12, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	0.0030
Dann	Benign	0.21
DEOGEN2	Benign	0.020	T;T;.;T;.;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.34	T;T;T;T;T;T
MetaRNN	Benign	0.0022	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.1	N;N;.;N;N;N
REVEL	Benign	0.053
Sift	Benign	0.12	T;T;.;T;D;T
Sift4G	Benign	0.070	T;T;T;T;T;T
Polyphen		0.017, 0.050, 0.13	.;.;.;B;B;B
Vest4		0.039, 0.021, 0.063, 0.059
MPC		0.058
ClinPred		0.018	T
GERP RS		-7.9
Varity_R		0.020
gMVP		0.067

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: rs12128607; hg19: chr1-186275564; COSMIC: COSV104422653;