11-57376864-C-G

Variant summary

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

The NM_006093.4(PRG3):​c.664G>C​(p.Val222Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,612,542 control chromosomes in the GnomAD database, with no homozygous occurrence. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V222I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PRG3
NM_006093.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -4.05
Variant links:
Genes affected
PRG3 (HGNC:9363): (proteoglycan 3, pro eosinophil major basic protein 2) An extracellular matrix structural constituent conferring compression resistance. Involved in several processes, including granulocyte activation; histamine biosynthetic process; and regulation of gene expression. Located in collagen-containing extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
PRG3NM_006093.4 linkc.664G>C p.Val222Leu missense_variant Exon 6 of 6 ENST00000287143.2 NP_006084.2 Q9Y2Y8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRG3ENST00000287143.2 linkc.664G>C p.Val222Leu missense_variant Exon 6 of 6 1 NM_006093.4 ENSP00000287143.2 Q9Y2Y8

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152068
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000390
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000400
AC:
1
AN:
250124
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135644
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000887
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1460356
Hom.:
0
Cov.:
31
AF XY:
0.0000138
AC XY:
10
AN XY:
726450
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000378
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152186
Hom.:
0
Cov.:
30
AF XY:
0.0000134
AC XY:
1
AN XY:
74386
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000391
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 16, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.664G>C (p.V222L) alteration is located in exon 6 (coding exon 5) of the PRG3 gene. This alteration results from a G to C substitution at nucleotide position 664, causing the valine (V) at amino acid position 222 to be replaced by a leucine (L). 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
0.26
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
0.094
DANN
Benign
0.90
DEOGEN2
Benign
0.0081
T
Eigen
Benign
-0.86
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.041
N
LIST_S2
Benign
0.40
T
M_CAP
Benign
0.030
D
MetaRNN
Uncertain
0.45
T
MetaSVM
Benign
-0.79
T
MutationAssessor
Benign
1.9
M
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.22
Sift
Uncertain
0.024
D
Sift4G
Uncertain
0.046
D
Polyphen
0.96
D
Vest4
0.35
MutPred
0.78
Loss of methylation at K217 (P = 0.0966);
MVP
0.24
MPC
0.13
ClinPred
0.42
T
GERP RS
-7.0
Varity_R
0.12
gMVP
0.51

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
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.

Other links and lift over

dbSNP: rs897769972; hg19: chr11-57144337; API