Genetic Variant PRB1:p.Lys137Met (chr12-11353294-T-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000500254.6(PRB1):c.410A>T(p.Lys137Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000804 in 1,580,246 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000064 ( 1 hom., cov: 21)

Exomes 𝑓: 0.000082 ( 10 hom. )

Consequence

PRB1
ENST00000500254.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.130

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 was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18677872).

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRB1	NR_160307.2 link	n.847A>T		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.410A>T	p.Lys137Met	missense_variant	Exon 4 of 5	1	ENSP00000420826.2	A0A4W8X8U3
PRB1	ENST00000545626.5 link	c.350A>T	p.Lys117Met	missense_variant	Exon 4 of 5	1	ENSP00000444249.1	G3V1R1
PRB1	ENST00000240636.10 link	n.*353A>T		non_coding_transcript_exon_variant	Exon 3 of 4	1	ENSP00000485971.1	A0A0D9SET1
PRB1	ENST00000240636.10 link	n.*353A>T		3_prime_UTR_variant	Exon 3 of 4	1	ENSP00000485971.1	A0A0D9SET1

Frequencies

GnomAD3 genomes

AF:

0.0000637

AC:

AN:

141302

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000137

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000561

AC:

AN:

249718

AF XY:

0.0000444

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000820

AC:

118

AN:

1438944

Hom.:

Cov.:

AF XY:

0.0000768

AC XY:

AN XY:

716210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31518

American (AMR)

AF:

0.00

AC:

AN:

43262

Ashkenazi Jewish (ASJ)

AF:

0.0000395

AC:

AN:

25322

East Asian (EAS)

AF:

0.00

AC:

AN:

38620

South Asian (SAS)

AF:

0.00

AC:

AN:

85594

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52640

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5616

European-Non Finnish (NFE)

AF:

0.000102

AC:

112

AN:

1097404

Other (OTH)

AF:

0.0000848

AC:

AN:

58968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000637

AC:

AN:

141302

Hom.:

Cov.:

AF XY:

0.0000872

AC XY:

AN XY:

68826

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

35106

American (AMR)

AF:

0.00

AC:

AN:

14436

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3392

East Asian (EAS)

AF:

0.00

AC:

AN:

5040

South Asian (SAS)

AF:

0.00

AC:

AN:

4554

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9934

Middle Eastern (MID)

AF:

0.00

AC:

AN:

300

European-Non Finnish (NFE)

AF:

0.000137

AC:

AN:

65694

Other (OTH)

AF:

0.00

AC:

AN:

1948

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.418

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000212

Hom.:

ExAC

AF:

0.0000579

AC:

EpiCase

AF:

0.000274

EpiControl

AF:

0.000357

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 07, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.809A>T (p.K270M) alteration is located in exon 3 (coding exon 3) of the PRB1 gene. This alteration results from a A to T substitution at nucleotide position 809, causing the lysine (K) at amino acid position 270 to be replaced by a methionine (M). 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

-0.43

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.014

.;.;T

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.0063

M_CAP

Benign

0.00055

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Benign

-1.1

PhyloP100

-0.13

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.9

N;N;.

REVEL

Benign

0.035

Sift

Uncertain

0.0050

D;D;.

Sift4G

Uncertain

0.024

D;D;D

Polyphen

0.98

D;.;.

Vest4

0.23

MVP

0.20

MPC

0.069

ClinPred

0.062

GERP RS

0.046

gMVP

0.054

Mutation Taster

=100/0

polymorphism

(source)

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

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12-11353294-T-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over