Genetic Variant PRB1:p.Ser136Asn (chr12-11353297-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

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

The ENST00000500254.6(PRB1):c.407G>A(p.Ser136Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000076 ( 0 hom., cov: 21)

Exomes 𝑓: 0.000013 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PRB1
ENST00000500254.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.169

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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030222505).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRB1	NR_160307.2 link	n.844G>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.407G>A	p.Ser136Asn	missense_variant	Exon 4 of 5	1	ENSP00000420826.2	A0A4W8X8U3
PRB1	ENST00000545626.5 link	c.347G>A	p.Ser116Asn	missense_variant	Exon 4 of 5	1	ENSP00000444249.1	G3V1R1
PRB1	ENST00000240636.10 link	n.*350G>A		non_coding_transcript_exon_variant	Exon 3 of 4	1	ENSP00000485971.1	A0A0D9SET1
PRB1	ENST00000240636.10 link	n.*350G>A		3_prime_UTR_variant	Exon 3 of 4	1	ENSP00000485971.1	A0A0D9SET1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

130948

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000317

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000149

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000244

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000964

Gnomad OTH

AF:

0.000559

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000126

AC:

AN:

1429218

Hom.:

Cov.:

AF XY:

0.0000141

AC XY:

AN XY:

711442

show subpopulations

Gnomad4 AFR exome

AF:

0.0000324

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000128

Gnomad4 OTH exome

AF:

0.0000344

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000763

AC:

AN:

131054

Hom.:

Cov.:

AF XY:

0.0000627

AC XY:

AN XY:

63788

show subpopulations

Gnomad4 AFR

AF:

0.0000316

Gnomad4 AMR

AF:

0.000149

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000245

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000804

Gnomad4 OTH

AF:

0.000552

Alfa

AF:

0.000133

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.806G>A (p.S269N) 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 806, causing the serine (S) at amino acid position 269 to be replaced by an asparagine (N). 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

-0.44

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.038

DANN

Benign

0.12

DEOGEN2

Benign

0.00097

.;.;T

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.00067

M_CAP

Benign

0.00057

MetaRNN

Benign

0.030

T;T;T

MetaSVM

Benign

-0.94

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.43

N;N;.

REVEL

Benign

0.0040

Sift

Benign

1.0

T;T;.

Sift4G

Benign

0.69

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.13

MutPred

0.24

.;Loss of phosphorylation at S136 (P = 0.0043);.;

MVP

0.014

MPC

0.052

ClinPred

0.032

GERP RS

-1.6

gMVP

0.010

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