1-186312268-C-T

Position:

chr1-186312268-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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 (no stars). 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

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.670

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:

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]

TPR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 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 no_assertion_criteria_provided, 0 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 GnomAd4 at 164 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRG4	NM_005807.6 linkuse as main transcript	c.3887C>T	p.Thr1296Met	missense_variant	11/13	ENST00000445192.7	NP_005798.3
TPR	NM_003292.3 linkuse as main transcript	c.*1703G>A		3_prime_UTR_variant	51/51	ENST00000367478.9	NP_003283.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRG4	ENST00000445192.7 linkuse as main transcript	c.3887C>T	p.Thr1296Met	missense_variant	11/13	5	NM_005807.6	ENSP00000399679	P2	Q92954-1
TPR	ENST00000367478.9 linkuse as main transcript	c.*1703G>A		3_prime_UTR_variant	51/51	1	NM_003292.3	ENSP00000356448	P1	P12270-1

Frequencies

GnomAD3 genomes

AF:

0.0441

AC:

6704

AN:

152078

Hom.:

162

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0468

AC XY:

34007

AN XY:

727114

show subpopulations

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.:

AF XY:

0.0433

AC XY:

3219

AN XY:

74412

show subpopulations

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:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

PRG4-related disorder

Benign:1

Benign, no assertion criteria provided

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

BayesDel_noAF

Benign

-0.69

CADD

Benign

7.5

DANN

Benign

0.88

DEOGEN2

Benign

0.094

.;T;.;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.69

T;T;T;T

MetaRNN

Benign

0.0018

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

.;L;.;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.0

.;D;D;D

REVEL

Benign

0.063

Sift

Benign

0.050

.;D;D;D

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

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

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