chr1-186312792-G-A

Position:

• chr1-186312792-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005807.6(PRG4):​c.4015G>A​(p.Val1339Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,612,980 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (1 hom.)
• Consequence: PRG4 NM_005807.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.123

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.045499474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRG4	NM_005807.6	c.4015G>A	p.Val1339Met	missense_variant	12/13	ENST00000445192.7	NP_005798.3
TPR	NM_003292.3	c.*1179C>T		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	c.4015G>A	p.Val1339Met	missense_variant	12/13	5	NM_005807.6	ENSP00000399679	P2
TPR	ENST00000367478.9	c.*1179C>T		3_prime_UTR_variant	51/51	1	NM_003292.3	ENSP00000356448	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152140 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251312 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135830

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1460722 Hom.: 1 Cov.: 30 AF XY: 0.0000358 AC XY: 26 AN XY: 726728

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.000828

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152258 Hom.: 1 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74440

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.000102

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.00376 AC: 13 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2021

The c.4015G>A (p.V1339M) alteration is located in exon 12 (coding exon 11) of the PRG4 gene. This alteration results from a G to A substitution at nucleotide position 4015, causing the valine (V) at amino acid position 1339 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.062	.;T;.;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.80	T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.045	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.23	.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.9	.;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.19	.;T;T;T
Sift4G	Benign	0.50	T;T;T;T
Polyphen		0.84, 0.84, 0.69	.;P;P;P
Vest4		0.16
MVP		0.12
MPC		0.036
ClinPred		0.062	T
GERP RS		-1.1
Varity_R		0.036
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs370271535; hg19: chr1-186281924;