12-11268067-G-C

Position:

• chr12-11268067-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001394862.1(PRB3):​c.182C>G​(p.Pro61Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 150,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 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. P61T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00028 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRB3 NM_001394862.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.144

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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017073065).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRB3	NM_001394862.1	c.182C>G	p.Pro61Arg	missense_variant	3/4	ENST00000538488.3
LOC107987435	XR_007063209.1	n.761-9403G>C		intron_variant, non_coding_transcript_variant
PRB3	NM_006249.5	c.182C>G	p.Pro61Arg	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRB3	ENST00000538488.3	c.182C>G	p.Pro61Arg	missense_variant	3/4	5	NM_001394862.1	P1
PRB3	ENST00000539835.1	n.189C>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 192 AN: 150870 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000925

Gnomad ASJ AF: 0.000580

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000423

Gnomad FIN AF: 0.000478

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000828

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.000284 AC: 71 AN: 249842 Hom.: 0 AF XY: 0.000288 AC XY: 39 AN XY: 135420

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000295

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.000330

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000275 AC: 399 AN: 1449996 Hom.: 1 Cov.: 41 AF XY: 0.000274 AC XY: 198 AN XY: 721350

Gnomad4 AFR exome AF: 0.00172

Gnomad4 AMR exome AF: 0.000203

Gnomad4 ASJ exome AF: 0.000272

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.000187

Gnomad4 FIN exome AF: 0.000510

Gnomad4 NFE exome AF: 0.000240

Gnomad4 OTH exome AF: 0.000285

GnomAD4 genome AF: 0.00127 AC: 192 AN: 150980 Hom.: 0 Cov.: 28 AF XY: 0.00144 AC XY: 106 AN XY: 73758

Gnomad4 AFR AF: 0.00270

Gnomad4 AMR AF: 0.000924

Gnomad4 ASJ AF: 0.000580

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.000423

Gnomad4 FIN AF: 0.000478

Gnomad4 NFE AF: 0.000828

Gnomad4 OTH AF: 0.000476

Alfa AF: 0.00108 Hom.: 0

ExAC AF: 0.000346 AC: 42

EpiCase AF: 0.000383

EpiControl AF: 0.000119

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

Aug 09, 2021

The c.182C>G (p.P61R) alteration is located in exon 3 (coding exon 3) of the PRB3 gene. This alteration results from a C to G substitution at nucleotide position 182, causing the proline (P) at amino acid position 61 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	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	6.0
DANN	Benign	0.11
DEOGEN2	Benign	0.047	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0086	N
M_CAP	Benign	0.00086	T
MetaRNN	Benign	0.017	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.011
Sift4G	Uncertain	0.0060	D;D
Vest4		0.15
MVP		0.040
MPC		0.35
ClinPred		0.020	T
GERP RS		-0.41
gMVP		0.23

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: rs200423165; hg19: chr12-11421001;