Genetic Variant PLPBP:p.Pro87Arg (chr8-37766296-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM5

The NM_007198.4(PLPBP):c.260C>G(p.Pro87Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,050 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P87L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PLPBP
NM_007198.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.52

Publications

0 publications found

Variant links:

Genes affected

PLPBP (HGNC:9457): (pyridoxal phosphate binding protein) This gene encodes a pyridoxal 5'-phosphate binding protein involved in the homeostatic regulation of intracellular pyridoxal 5'-phosphate. This gene has a tumor suppressive effect on hepatocellular carcinoma and other solid tumors of epithelial origin. Naturally occurring mutations in this gene are associated with a pyridoxine-dependent epilepsy. [provided by RefSeq, Mar 2017]

PLPBP Gene-Disease associations (from GenCC):

epilepsy, early-onset, vitamin B6-dependent
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
pyridoxine-dependent epilepsy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PLPBP links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-37766296-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLPBP	NM_007198.4 link	c.260C>G	p.Pro87Arg	missense_variant	Exon 4 of 8	ENST00000328195.8	NP_009129.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLPBP	ENST00000328195.8 link	c.260C>G	p.Pro87Arg	missense_variant	Exon 4 of 8	1	NM_007198.4	ENSP00000333551.3		O94903

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457050

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724844

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33086

American (AMR)

AF:

0.00

AC:

AN:

43858

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26050

East Asian (EAS)

AF:

0.00

AC:

AN:

39396

South Asian (SAS)

AF:

0.00

AC:

AN:

85488

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109836

Other (OTH)

AF:

0.00

AC:

AN:

60214

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;T;.;T

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.61

D;D;D;D

MetaSVM

Benign

-0.89

PhyloP100

7.5

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.2

D;D;D;D

REVEL

Benign

0.28

Sift

Benign

0.082

T;T;T;D

Sift4G

Benign

0.11

T;T;T;T

Polyphen

0.018

B;.;.;.

Vest4

0.73

MutPred

0.62

Gain of sheet (P = 0.0049);Gain of sheet (P = 0.0049);.;.;

MVP

0.46

MPC

0.88

ClinPred

0.94

GERP RS

5.3

PromoterAI

0.041

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.55

gMVP

0.67

Mutation Taster

=20/80

disease causing

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over