NM_007198.4:c.19A>T

Variant names:

• chr8-37762678-A-T
• rs764612461
• NM_007198.4:c.19A>T

Variant summary

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

The NM_007198.4(PLPBP):​c.19A>T​(p.Met7Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,435,270 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). 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. M7V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLPBP NM_007198.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.29
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.19A>T	p.Met7Leu	missense	Exon 1 of 8	NP_009129.1	O94903
	PLPBP	NM_001349348.2		c.-80A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001336277.1
	PLPBP	NM_001349346.2		c.19A>T	p.Met7Leu	missense	Exon 1 of 8	NP_001336275.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLPBP	ENST00000328195.8	TSL:1 MANE Select	c.19A>T	p.Met7Leu	missense	Exon 1 of 8	ENSP00000333551.3	O94903
	PLPBP	ENST00000523187.5	TSL:3	c.-80A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000427886.1	E5RFX7
	PLPBP	ENST00000872272.1		c.19A>T	p.Met7Leu	missense	Exon 1 of 8	ENSP00000542331.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1435270 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 711974

African (AFR) AF: 0.00 AC: 0 AN: 33242

American (AMR) AF: 0.00 AC: 0 AN: 40676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25582

East Asian (EAS) AF: 0.00 AC: 0 AN: 38892

South Asian (SAS) AF: 0.00 AC: 0 AN: 82780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5324

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102658

Other (OTH) AF: 0.00 AC: 0 AN: 59522

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Epilepsy, early-onset, vitamin B6-dependent (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.045
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-1.0	T
PhyloP100		5.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.16
Sift	Benign	0.096	T
Sift4G	Uncertain	0.042	D
Polyphen		0.036	B
Vest4		0.60
MutPred		0.42		Loss of MoRF binding (P = 0.0708)
MVP		0.39
MPC		0.36
ClinPred		0.85	D
GERP RS		5.5
PromoterAI		-0.28	Neutral
Varity_R		0.72
gMVP		0.65
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs764612461; hg19: chr8-37620196;