12-11267429-C-T

Position:

• chr12-11267429-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_001394862.1(PRB3):​c.820G>A​(p.Gly274Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000459 in 1,567,270 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (4 hom., cov: 25)
  • Exomes 𝑓: 0.00048 (20 hom.)
• Consequence: PRB3 NM_001394862.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.37

Genes affected

PRB3 (HGNC:9339): (proline rich protein BstNI subfamily 3) This gene encodes a member of the heterogeneous family of basic, proline-rich, human salivary glycoproteins. Multiple alleles of this gene exhibiting variations in the length of the tandem repeats have been identified. The reference genome encodes the "Long" allele. The protein isoforms encoded by this gene are recognized as the "first line of oral defense" against the detrimental effects of polyphenols in the diet and pathogen infections. This gene is located in a cluster of closely related salivary proline-rich proteins on chromosome 12. [provided by RefSeq, Nov 2015]

LOC107987435 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.036661386).
• BS2: High Homozygotes in GnomAd4 at 4 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRB3	NM_001394862.1	c.820G>A	p.Gly274Arg	missense_variant	3/4	ENST00000538488.3	NP_001381791.1
PRB3	NM_006249.5	c.694G>A	p.Gly232Arg	missense_variant	4/5		NP_006240.4
LOC107987435	XR_007063209.1	n.761-10041C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRB3	ENST00000538488.3	c.820G>A	p.Gly274Arg	missense_variant	3/4	5	NM_001394862.1	ENSP00000442626.2

Frequencies

GnomAD3 genomes AF: 0.000275 AC: 40 AN: 145596 Hom.: 4 Cov.: 25

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000406

Gnomad ASJ AF: 0.000592

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000996

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000472

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000230 AC: 57 AN: 248308 Hom.: 0 AF XY: 0.000230 AC XY: 31 AN XY: 134654

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.000300

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000338

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000478 AC: 680 AN: 1421674 Hom.: 20 Cov.: 34 AF XY: 0.000453 AC XY: 319 AN XY: 704758

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.000319

Gnomad4 ASJ exome AF: 0.000198

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000380

Gnomad4 FIN exome AF: 0.0000792

Gnomad4 NFE exome AF: 0.000567

Gnomad4 OTH exome AF: 0.000496

GnomAD4 genome AF: 0.000275 AC: 40 AN: 145596 Hom.: 4 Cov.: 25 AF XY: 0.000339 AC XY: 24 AN XY: 70782

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000406

Gnomad4 ASJ AF: 0.000592

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000996

Gnomad4 NFE AF: 0.000472

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000491 Hom.: 0

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.000583 AC: 5

ExAC AF: 0.000582 AC: 42

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

The c.694G>A (p.G232R) alteration is located in exon 4 (coding exon 4) of the PRB3 gene. This alteration results from a G to A substitution at nucleotide position 694, causing the glycine (G) at amino acid position 232 to be replaced by an arginine (R). 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
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	15
DANN	Benign	0.38
DEOGEN2	Benign	0.028	T;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0032	N
M_CAP	Benign	0.00056	T
MetaRNN	Benign	0.037	T;T
MetaSVM	Benign	-0.90	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.054
Sift4G	Uncertain	0.031	D;T
Vest4		0.11
MutPred		0.33		Gain of catalytic residue at P228 (P = 5e-04);.;
MVP		0.16
MPC		0.39
ClinPred		0.039	T
GERP RS		0.068
gMVP		0.089

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: rs369321112; hg19: chr12-11420363;