NM_005807.6:c.3887C>T

Variant names:

• chr1-186312268-C-T
• rs12134934
• NM_005807.6:c.3887C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.044 (164 hom., cov: 32)
  • Exomes 𝑓: 0.047 (1775 hom.)
• Consequence: PRG4 NM_005807.6 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.670
• Publications: 10 publications found

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]

TPR Gene-Disease associations (from GenCC):

• intellectual developmental disorder, autosomal recessive 79

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 3037358.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 164 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005807.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRG4	NM_005807.6	MANE Select	c.3887C>T	p.Thr1296Met	missense	Exon 11 of 13	NP_005798.3	Q92954-1
	TPR	NM_003292.3	MANE Select	c.*1703G>A		3_prime_UTR	Exon 51 of 51	NP_003283.2	P12270-1
	PRG4	NM_001127708.3		c.3764C>T	p.Thr1255Met	missense	Exon 10 of 12	NP_001121180.2	Q92954-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRG4	ENST00000445192.7	TSL:5 MANE Select	c.3887C>T	p.Thr1296Met	missense	Exon 11 of 13	ENSP00000399679.3	Q92954-1
	TPR	ENST00000367478.9	TSL:1 MANE Select	c.*1703G>A		3_prime_UTR	Exon 51 of 51	ENSP00000356448.3	P12270-1
	PRG4	ENST00000367483.8	TSL:5	c.3764C>T	p.Thr1255Met	missense	Exon 10 of 12	ENSP00000356453.4	Q92954-2

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

GnomAD2 exomes AF: 0.0395 AC: 9910 AN: 250720 AF XY: 0.0407

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 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

African (AFR) AF: 0.0507 AC: 1697 AN: 33468

American (AMR) AF: 0.0123 AC: 549 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0154 AC: 402 AN: 26126

East Asian (EAS) AF: 0.000428 AC: 17 AN: 39682

South Asian (SAS) AF: 0.0451 AC: 3888 AN: 86238

European-Finnish (FIN) AF: 0.0719 AC: 3841 AN: 53398

Middle Eastern (MID) AF: 0.0291 AC: 168 AN: 5768

European-Non Finnish (NFE) AF: 0.0495 AC: 55049 AN: 1111830

Other (OTH) AF: 0.0415 AC: 2503 AN: 60384

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

African (AFR) AF: 0.0462 AC: 1919 AN: 41514

American (AMR) AF: 0.0170 AC: 260 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5186

South Asian (SAS) AF: 0.0439 AC: 212 AN: 4824

European-Finnish (FIN) AF: 0.0741 AC: 784 AN: 10582

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0485 AC: 3300 AN: 68024

Other (OTH) AF: 0.0360 AC: 76 AN: 2110

Alfa AF: 0.0435 Hom.: 715

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

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PRG4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.094	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.67
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.063
Sift	Benign	0.050	D
Sift4G	Benign	0.092	T
Polyphen		0.93	P
Vest4		0.13
MPC		0.036
ClinPred		0.054	T
GERP RS		-1.6
Varity_R		0.027
gMVP		0.30
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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