Genetic Variant PRB1:p.Arg192Lys (chr12-11353129-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000500254.6(PRB1):c.575G>A(p.Arg192Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000925 in 1,405,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 11)

Exomes 𝑓: 0.0000092 ( 0 hom. )

Consequence

PRB1
ENST00000500254.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.45

Variant links:

Genes affected

PRB1 (HGNC:9337): (proline rich protein BstNI subfamily 1) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

PRB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.027106434).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRB1	NR_160307.2 link	n.1012G>A		non_coding_transcript_exon_variant	Exon 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
PRB1	ENST00000500254.6 link	c.575G>A	p.Arg192Lys	missense_variant	Exon 4 of 5	1	ENSP00000420826.2	A0A4W8X8U3
PRB1	ENST00000545626.5 link	c.515G>A	p.Arg172Lys	missense_variant	Exon 4 of 5	1	ENSP00000444249.1	G3V1R1
PRB1	ENST00000240636.10 link	n.*518G>A		non_coding_transcript_exon_variant	Exon 3 of 4	1	ENSP00000485971.1	A0A0D9SET1
PRB1	ENST00000240636.10 link	n.*518G>A		3_prime_UTR_variant	Exon 3 of 4	1	ENSP00000485971.1	A0A0D9SET1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000499

AC:

AN:

200550

Hom.:

AF XY:

0.0000462

AC XY:

AN XY:

108232

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:

0.000433

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000925

AC:

AN:

1405526

Hom.:

Cov.:

AF XY:

0.00000719

AC XY:

AN XY:

695756

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000158

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000586

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.974G>A (p.R325K) alteration is located in exon 3 (coding exon 3) of the PRB1 gene. This alteration results from a G to A substitution at nucleotide position 974, causing the arginine (R) at amino acid position 325 to be replaced by a lysine (K). 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

-0.58

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.14

DANN

Benign

0.17

DEOGEN2

Benign

0.0064

.;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0012

M_CAP

Benign

0.0011

MetaRNN

Benign

0.027

T;T;T

MetaSVM

Benign

-0.92

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.44

N;N;.

REVEL

Benign

0.0050

Sift

Benign

0.96

T;T;.

Sift4G

Benign

1.0

T;T;T

Polyphen

0.31

B;.;.

Vest4

0.082

MutPred

0.33

.;Gain of catalytic residue at P187 (P = 0);.;

MVP

0.014

MPC

0.055

ClinPred

0.027

GERP RS

-0.79

gMVP

0.061

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over