1-186312345-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BS1_Supporting
The NM_005807.6(PRG4):c.3964C>T(p.Pro1322Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000526 in 1,608,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00056 ( 0 hom. )
Consequence
PRG4
NM_005807.6 missense
NM_005807.6 missense
Scores
4
10
Clinical Significance
Conservation
PhyloP100: 2.12
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.34912553).
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000557 (812/1456540) while in subpopulation NFE AF= 0.000709 (787/1110252). AF 95% confidence interval is 0.000667. There are 0 homozygotes in gnomad4_exome. There are 371 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| PRG4 | NM_005807.6 | c.3964C>T | p.Pro1322Ser | missense_variant | 11/13 | ENST00000445192.7 | |
| TPR | NM_003292.3 | c.*1626G>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.3964C>T | p.Pro1322Ser | missense_variant | 11/13 | 5 | NM_005807.6 | P2 | |
| TPR | ENST00000367478.9 | c.*1626G>A | 3_prime_UTR_variant | 51/51 | 1 | NM_003292.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000223 AC: 34AN: 152130Hom.: 0 Cov.: 32
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?
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GnomAD3 exomes AF: 0.000232 AC: 57AN: 245872Hom.: 0 AF XY: 0.000256 AC XY: 34AN XY: 132794
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GnomAD4 exome AF: 0.000557 AC: 812AN: 1456540Hom.: 0 Cov.: 31 AF XY: 0.000512 AC XY: 371AN XY: 724184
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GnomAD4 genome ? AF: 0.000223 AC: 34AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74330
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 26, 2022 | The c.3964C>T (p.P1322S) alteration is located in exon 11 (coding exon 10) of the PRG4 gene. This alteration results from a C to T substitution at nucleotide position 3964, causing the proline (P) at amino acid position 1322 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Benign
T
Sift4G
Benign
T;D;D;T
Polyphen
1.0, 1.0
.;D;D;D
Vest4
MVP
0.13
MPC
0.036
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at