8-37762667-G-C

Variant names:

• chr8-37762667-G-C
• rs982521520
• NM_007198.4:c.8G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007198.4(PLPBP):​c.8G>C​(p.Arg3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000629 in 1,430,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. R3K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: PLPBP NM_007198.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.43
• Publications: 0 publications found

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

ENSG00000304882 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19834518).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007198.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLPBP	NM_007198.4	MANE Select	c.8G>C	p.Arg3Thr	missense	Exon 1 of 8	NP_009129.1	O94903
	PLPBP	NM_001349346.2		c.8G>C	p.Arg3Thr	missense	Exon 1 of 8	NP_001336275.1
	PLPBP	NM_001349347.2		c.8G>C	p.Arg3Thr	missense	Exon 1 of 8	NP_001336276.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLPBP	ENST00000328195.8	TSL:1 MANE Select	c.8G>C	p.Arg3Thr	missense	Exon 1 of 8	ENSP00000333551.3	O94903
	PLPBP	ENST00000872272.1		c.8G>C	p.Arg3Thr	missense	Exon 1 of 8	ENSP00000542331.1
	PLPBP	ENST00000958638.1		c.8G>C	p.Arg3Thr	missense	Exon 1 of 8	ENSP00000628697.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000510 AC: 1 AN: 196254 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000346

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000629 AC: 9 AN: 1430276 Hom.: 0 Cov.: 34 AF XY: 0.00000423 AC XY: 3 AN XY: 708970

African (AFR) AF: 0.00 AC: 0 AN: 33194

American (AMR) AF: 0.0000251 AC: 1 AN: 39772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25514

East Asian (EAS) AF: 0.00 AC: 0 AN: 38682

South Asian (SAS) AF: 0.00 AC: 0 AN: 82262

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5360

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099978

Other (OTH) AF: 0.000135 AC: 8 AN: 59378

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.043
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.98	T
PhyloP100		1.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.069
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.016	D
Polyphen		0.18	B
Vest4		0.50
MVP		0.43
MPC		0.86
ClinPred		0.84	D
GERP RS		3.3
PromoterAI		-0.21	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.21
gMVP		0.75
Mutation Taster		=50/50

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

Other links and lift over

dbSNP: rs982521520; hg19: chr8-37620185;