8-37766296-C-G

Variant names:

• chr8-37766296-C-G
• NM_007198.4:c.260C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

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 Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PLPBP NM_007198.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.52

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Pyridoxal phosphate homeostasis protein (size 274) in uniprot entity PLPHP_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_007198.4
• 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 Lovd as [Pathogenic].

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457050 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724844

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
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	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.61	D;D;D;D
MetaSVM	Benign	-0.89	T
PrimateAI	Uncertain	0.69	T
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	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.55
gMVP		0.67

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-37623814;