1-186306378-A-C

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.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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.520

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=0.006234437).
• 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_single_submitter, 1 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 GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRG4	NM_005807.6	c.659A>C	p.Asp220Ala	missense_variant	7/13	ENST00000445192.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRG4	ENST00000445192.7	c.659A>C	p.Asp220Ala	missense_variant	7/13	5	NM_005807.6	P2

Frequencies

GnomAD3 genomes AF: 0.00678 AC: 1031 AN: 152124 Hom.: 13 Cov.: 32

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.: 7 AF XY: 0.00161 AC XY: 218 AN XY: 135508

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.: 20 Cov.: 31 AF XY: 0.000827 AC XY: 601 AN XY: 726630

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.: 13 Cov.: 32 AF XY: 0.00668 AC XY: 497 AN XY: 74450

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.: 3

Bravo AF: 0.00763

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0193 AC: 85

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00241 AC: 292

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 08, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	23
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	N
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	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.32	T
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	T
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

Other links and lift over

dbSNP: rs114532084; hg19: chr1-186275510; COSMIC: COSV104422668;