1-186312268-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.3887C>T(p.Thr1296Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0464 in 1,613,812 control chromosomes in the GnomAD database, including 1,939 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.044 (164 hom., cov: 32)
  • Exomes 𝑓: 0.047 (1775 hom.)
• Consequence: PRG4 NM_005807.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.670

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]

TPR (HGNC:12017): (translocated promoter region, nuclear basket protein) This gene encodes a large coiled-coil protein that forms intranuclear filaments attached to the inner surface of nuclear pore complexes (NPCs). The protein directly interacts with several components of the NPC. It is required for the nuclear export of mRNAs and some proteins. Oncogenic fusions of the 5' end of this gene with several different kinase genes occur in some neoplasias. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017856956).
• BP6: Variant 1-186312268-C-T is Benign according to our data. Variant chr1-186312268-C-T is described in ClinVar as [Benign]. Clinvar id is 3037358.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-186312268-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0441 (6715/152196) while in subpopulation NFE AF= 0.0485 (3300/68024). AF 95% confidence interval is 0.0471. There are 164 homozygotes in gnomad4. There are 3219 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 162 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRG4	NM_005807.6	c.3887C>T	p.Thr1296Met	missense_variant	11/13	ENST00000445192.7
TPR	NM_003292.3	c.*1703G>A		3_prime_UTR_variant	51/51	ENST00000367478.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRG4	ENST00000445192.7	c.3887C>T	p.Thr1296Met	missense_variant	11/13	5	NM_005807.6	P2
TPR	ENST00000367478.9	c.*1703G>A		3_prime_UTR_variant	51/51	1	NM_003292.3	P1

Frequencies

GnomAD3 genomes AF: 0.0441 AC: 6704 AN: 152078 Hom.: 162 Cov.: 32

Gnomad AFR AF: 0.0461

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.0171

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0439

Gnomad FIN AF: 0.0741

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0485

Gnomad OTH AF: 0.0364

GnomAD3 exomes AF: 0.0395 AC: 9910 AN: 250720 Hom.: 256 AF XY: 0.0407 AC XY: 5522 AN XY: 135622

Gnomad AFR exome AF: 0.0476

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.0158

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0455

Gnomad FIN exome AF: 0.0728

Gnomad NFE exome AF: 0.0476

Gnomad OTH exome AF: 0.0357

GnomAD4 exome AF: 0.0466 AC: 68114 AN: 1461616 Hom.: 1775 Cov.: 31 AF XY: 0.0468 AC XY: 34007 AN XY: 727114

Gnomad4 AFR exome AF: 0.0507

Gnomad4 AMR exome AF: 0.0123

Gnomad4 ASJ exome AF: 0.0154

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.0451

Gnomad4 FIN exome AF: 0.0719

Gnomad4 NFE exome AF: 0.0495

Gnomad4 OTH exome AF: 0.0415

GnomAD4 genome AF: 0.0441 AC: 6715 AN: 152196 Hom.: 164 Cov.: 32 AF XY: 0.0433 AC XY: 3219 AN XY: 74412

Gnomad4 AFR AF: 0.0462

Gnomad4 AMR AF: 0.0170

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0439

Gnomad4 FIN AF: 0.0741

Gnomad4 NFE AF: 0.0485

Gnomad4 OTH AF: 0.0360

Alfa AF: 0.0431 Hom.: 412

Bravo AF: 0.0393

TwinsUK AF: 0.0464 AC: 172

ALSPAC AF: 0.0568 AC: 219

ESP6500AA AF: 0.0461 AC: 203

ESP6500EA AF: 0.0451 AC: 388

ExAC AF: 0.0404 AC: 4900

Asia WGS AF: 0.0240 AC: 84 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	0.15
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	7.5
Dann	Benign	0.88
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.69	T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.29	T
Sift4G	Benign	0.092	T;T;T;T
Polyphen		0.93, 0.96	.;P;D;D
Vest4		0.13
MPC		0.036
ClinPred		0.054	T
GERP RS		-1.6
Varity_R		0.027
gMVP		0.30

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: rs12134934; hg19: chr1-186281400; COSMIC: COSV104422654; COSMIC: COSV104422654;