Genetic Variant PBLD:p.Leu123Phe (chr10-68292153-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_022129.4(PBLD):c.369G>C(p.Leu123Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000851 in 1,613,910 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00062 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00088 ( 2 hom. )

Consequence

PBLD
NM_022129.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.672

Publications

2 publications found

Variant links:

Genes affected

PBLD (HGNC:23301): (phenazine biosynthesis like protein domain containing) Enables identical protein binding activity. Involved in maintenance of gastrointestinal epithelium; negative regulation of SMAD protein signal transduction; and negative regulation of transforming growth factor beta receptor signaling pathway. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PBLD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01686433).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PBLD	NM_022129.4 link	c.369G>C	p.Leu123Phe	missense_variant	Exon 5 of 10	ENST00000358769.7	NP_071412.2	P30039-1A0A024QZK5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PBLD	ENST00000358769.7 link	c.369G>C	p.Leu123Phe	missense_variant	Exon 5 of 10	5	NM_022129.4	ENSP00000351619.2		P30039-1

Frequencies

GnomAD3 genomes

AF:

0.000618

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000926

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000625

AC:

157

AN:

251106

AF XY:

0.000634

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000608

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000604

Gnomad NFE exome

AF:

0.00104

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000875

AC:

1279

AN:

1461640

Hom.:

Cov.:

AF XY:

0.000828

AC XY:

602

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000604

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.000431

AC:

AN:

53318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00108

AC:

1199

AN:

1111906

Other (OTH)

AF:

0.000431

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

125

187

250

312

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000617

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41556

American (AMR)

AF:

0.00118

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000926

AC:

AN:

68020

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000691

Hom.:

Bravo

AF:

0.000688

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000651

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000948

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 13, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.369G>C (p.L123F) alteration is located in exon 5 (coding exon 4) of the PBLD gene. This alteration results from a G to C substitution at nucleotide position 369, causing the leucine (L) at amino acid position 123 to be replaced by a phenylalanine (F). 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

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.071

(source)

DANN

Benign

0.13

DEOGEN2

Benign

0.046

T;T;T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.73

T;T;.;T

M_CAP

Benign

0.0048

MetaRNN

Benign

0.017

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

.;N;N;N

PhyloP100

-0.67

PrimateAI

Benign

0.28

PROVEAN

Benign

0.91

N;N;N;.

REVEL

Benign

0.086

Sift

Benign

0.92

T;T;T;.

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0010

.;B;B;.

Vest4

0.11

MutPred

0.64

.;Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);

MVP

0.040

MPC

0.20

ClinPred

0.0049

GERP RS

-7.3

Varity_R

0.063

gMVP

0.58

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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10-68292153-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over