8-37762678-A-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001349348.2(PLPBP):​c.-80A>T variant causes a 5 prime UTR premature start codon gain 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLPBP NM_001349348.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.29

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]

LOC124901934 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLPBP	NM_007198.4	c.19A>T	p.Met7Leu	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	c.19A>T	p.Met7Leu	missense_variant	Exon 1 of 8	1	NM_007198.4	ENSP00000333551.3

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

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

May 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with PROSC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 7 of the PROSC protein (p.Met7Leu). -

Epilepsy, early-onset, vitamin B6-dependent Uncertain:1

Nov 01, 2024

Neurogenetics Team, Indira Gandhi Institute of Child Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant identified is present at extremely low frequency in gnomAD. Multiple Insilico tools predict the variant to be tolerated. Currently there is insufficient evidence on the variant pathogenicity. Hence, this variant is being classified as Variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	0.045
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.16
Sift	Benign	0.096	T;D
Sift4G	Uncertain	0.042	D;T
Polyphen		0.036	B;.
Vest4		0.60
MutPred		0.42		Loss of MoRF binding (P = 0.0708);Loss of MoRF binding (P = 0.0708);
MVP		0.39
MPC		0.36
ClinPred		0.85	D
GERP RS		5.5
Varity_R		0.72
gMVP		0.65

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-37620196;