8-37762675-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_007198.4(PLPBP):c.16A>G(p.Ser6Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000976 in 1,434,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S6R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000098 (0 hom.)
• Consequence: PLPBP NM_007198.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0660

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.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity PLPHP_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.082062155).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLPBP	NM_007198.4	c.16A>G	p.Ser6Gly	missense_variant	1/8	ENST00000328195.8
LOC124901934	XR_007060889.1	n.477T>C		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLPBP	ENST00000328195.8	c.16A>G	p.Ser6Gly	missense_variant	1/8	1	NM_007198.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000148 AC: 3 AN: 202128 Hom.: 0 AF XY: 0.0000183 AC XY: 2 AN XY: 109448

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000630

Gnomad SAS exome AF: 0.0000375

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000112

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000976 AC: 14 AN: 1434290 Hom.: 0 Cov.: 34 AF XY: 0.0000127 AC XY: 9 AN XY: 711344

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.0000726

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000635

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000839 AC: 1

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 20, 2022

This variant has not been reported in the literature in individuals affected with PROSC-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 6 of the PROSC protein (p.Ser6Gly). 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 output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	8.6
Dann	Benign	0.97
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.082	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.73	N;N
REVEL	Benign	0.022
Sift	Benign	0.30	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.0	B;.
Vest4		0.19
MutPred		0.34		Loss of phosphorylation at S6 (P = 0.0322);Loss of phosphorylation at S6 (P = 0.0322);
MVP		0.27
MPC		0.35
ClinPred		0.086	T
GERP RS		1.2
Varity_R		0.075
gMVP		0.41

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

LitVar

Other links and lift over

dbSNP: rs568414778; hg19: chr8-37620193;