1-186312353-A-C

Variant names:

• chr1-186312353-A-C
• rs1657327056
• NM_005807.6:c.3972A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005807.6(PRG4):​c.3972A>C​(p.Arg1324Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRG4 NM_005807.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRG4	NM_005807.6	c.3972A>C	p.Arg1324Ser	missense_variant	Exon 11 of 13	ENST00000445192.7	NP_005798.3
TPR	NM_003292.3	c.*1618T>G		3_prime_UTR_variant	Exon 51 of 51	ENST00000367478.9	NP_003283.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRG4	ENST00000445192.7	c.3972A>C	p.Arg1324Ser	missense_variant	Exon 11 of 13	5	NM_005807.6	ENSP00000399679.3
TPR	ENST00000367478	c.*1618T>G		3_prime_UTR_variant	Exon 51 of 51	1	NM_003292.3	ENSP00000356448.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Sep 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3972A>C (p.R1324S) alteration is located in exon 11 (coding exon 10) of the PRG4 gene. This alteration results from a A to C substitution at nucleotide position 3972, causing the arginine (R) at amino acid position 1324 to be replaced by a serine (S). 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	Uncertain	0.44
BayesDel_addAF	Benign	-0.0070	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.33	.;T;.;.
Eigen	Benign	0.020
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.47	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	.;M;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.2	.;D;D;D
REVEL	Benign	0.091
Sift	Uncertain	0.0060	.;D;D;D
Sift4G	Uncertain	0.052	T;D;D;D
Polyphen		1.0, 0.98	.;D;D;D
Vest4		0.41
MutPred		0.47		.;Loss of MoRF binding (P = 0.0299);.;.;
MVP		0.18
MPC		0.038
ClinPred		0.95	D
GERP RS		3.8
Varity_R		0.092
gMVP		0.71

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: rs1657327056; hg19: chr1-186281485;