Genetic Variant PLPBP:p.Val24Leu (chr8-37762729-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_007198.4(PLPBP):c.70G>C(p.Val24Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,433,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V24M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PLPBP
NM_007198.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.61

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:

ENSG00000304882 (HGNC:):

ENSG00000304882 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34833664).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLPBP	NM_007198.4 link	c.70G>C	p.Val24Leu	missense_variant	Exon 1 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.70G>C	p.Val24Leu	missense_variant	Exon 1 of 8	1	NM_007198.4	ENSP00000333551.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1433276

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

711324

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33212

American (AMR)

AF:

0.00

AC:

AN:

41142

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25594

East Asian (EAS)

AF:

0.00

AC:

AN:

38910

South Asian (SAS)

AF:

0.00

AC:

AN:

82968

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43812

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5000

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1103156

Other (OTH)

AF:

0.00

AC:

AN:

59482

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.75

T;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.0

.;.

PhyloP100

4.6

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.13

Sift

Uncertain

0.019

D;D

Sift4G

Uncertain

0.031

D;T

Vest4

0.32

ClinPred

0.95

GERP RS

4.6

PromoterAI

0.036

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.35

gMVP

0.65

Mutation Taster

=85/15

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over