11-57376857-G-A

Variant names:

• chr11-57376857-G-A
• rs1856950092
• NM_006093.4:c.671C>T

Variant summary

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

The NM_006093.4(PRG3):​c.671C>T​(p.Ser224Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,116 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
• Consequence: PRG3 NM_006093.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.68

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]

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
PRG3	NM_006093.4	c.671C>T	p.Ser224Phe	missense_variant	Exon 6 of 6	ENST00000287143.2	NP_006084.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRG3	ENST00000287143.2	c.671C>T	p.Ser224Phe	missense_variant	Exon 6 of 6	1	NM_006093.4	ENSP00000287143.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74286

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.671C>T (p.S224F) alteration is located in exon 6 (coding exon 5) of the PRG3 gene. This alteration results from a C to T substitution at nucleotide position 671, causing the serine (S) at amino acid position 224 to be replaced by a phenylalanine (F). 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	0.53
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.064
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.11
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.41
MutPred		0.54		Loss of disorder (P = 0);
MVP		0.57
MPC		0.22
ClinPred		0.99	D
GERP RS		2.6
Varity_R		0.39
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1856950092; hg19: chr11-57144330;