Genetic Variant PRB1:p.Arg186His (chr12-11353147-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000500254.6(PRB1):c.557G>A(p.Arg186His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000386 in 1,528,526 control chromosomes in the GnomAD database, including 5 homozygotes. 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: 𝑓 0.000071 ( 0 hom., cov: 13)

Exomes 𝑓: 0.000036 ( 5 hom. )

Consequence

PRB1
ENST00000500254.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.88

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04758537).

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRB1	NR_160307.2 link	n.994G>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.557G>A	p.Arg186His	missense_variant	Exon 4 of 5	1	ENSP00000420826.2	A0A4W8X8U3
PRB1	ENST00000545626.5 link	c.497G>A	p.Arg166His	missense_variant	Exon 4 of 5	1	ENSP00000444249.1	G3V1R1
PRB1	ENST00000240636.10 link	n.*500G>A		non_coding_transcript_exon_variant	Exon 3 of 4	1	ENSP00000485971.1	A0A0D9SET1
PRB1	ENST00000240636.10 link	n.*500G>A		3_prime_UTR_variant	Exon 3 of 4	1	ENSP00000485971.1	A0A0D9SET1

Frequencies

GnomAD3 genomes

AF:

0.0000714

AC:

AN:

97984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000136

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00116

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:

0.000780

GnomAD3 exomes

AF:

0.0000493

AC:

AN:

223118

Hom.:

AF XY:

0.0000331

AC XY:

AN XY:

120918

show subpopulations

Gnomad AFR exome

AF:

0.000151

Gnomad AMR exome

AF:

0.000124

Gnomad ASJ exome

AF:

0.000124

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000370

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000301

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1430542

Hom.:

Cov.:

AF XY:

0.0000338

AC XY:

AN XY:

709978

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000914

Gnomad4 ASJ exome

AF:

0.000557

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000237

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000284

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

AF:

0.0000714

AC:

AN:

97984

Hom.:

Cov.:

AF XY:

0.0000425

AC XY:

AN XY:

47074

show subpopulations

Gnomad4 AFR

AF:

0.000136

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00116

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000780

Alfa

AF:

0.0000481

Hom.:

ExAC

AF:

0.0000417

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.956G>A (p.R319H) 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 956, causing the arginine (R) at amino acid position 319 to be replaced by a histidine (H). 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

-0.48

BayesDel_noAF

Benign

-0.67

CADD

Benign

4.9

DANN

Benign

0.81

DEOGEN2

Benign

0.0055

.;.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0021

M_CAP

Benign

0.0010

MetaRNN

Benign

0.048

T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.1

N;N;.

REVEL

Benign

0.087

Sift

Uncertain

0.025

D;D;.

Sift4G

Benign

0.084

T;T;D

Polyphen

0.73

P;.;.

Vest4

0.16

MutPred

0.34

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

MVP

0.055

MPC

0.065

ClinPred

0.031

GERP RS

-2.0

gMVP

0.035

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