rs35423325

chr8-37762729-G-Achr8-37762729-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007198.4(PLPBP):c.70G>A(p.Val24Met) variant causes a missense change. The variant allele was found at a frequency of 0.00173 in 1,585,556 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V24E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0093 (26 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (15 hom.)
• Consequence: PLPBP NM_007198.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.61

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007576108).
• BP6: Variant 8-37762729-G-A is Benign according to our data. Variant chr8-37762729-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00934 (1422/152286) while in subpopulation AFR AF= 0.0327 (1357/41558). AF 95% confidence interval is 0.0312. There are 26 homozygotes in gnomad4. There are 664 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLPBP	NM_007198.4	c.70G>A	p.Val24Met	missense_variant	1/8	ENST00000328195.8
LOC124901934	XR_007060889.1	n.423C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLPBP	ENST00000328195.8	c.70G>A	p.Val24Met	missense_variant	1/8	1	NM_007198.4	P1

Frequencies

GnomAD3 genomes AF: 0.00914 AC: 1391 AN: 152168 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0320

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00215 AC: 428 AN: 198810 Hom.: 6 AF XY: 0.00159 AC XY: 172 AN XY: 108074

Gnomad AFR exome AF: 0.0298

Gnomad AMR exome AF: 0.00161

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000678

Gnomad OTH exome AF: 0.000588

GnomAD4 exome AF: 0.000925 AC: 1326 AN: 1433270 Hom.: 15 Cov.: 34 AF XY: 0.000811 AC XY: 577 AN XY: 711322

Gnomad4 AFR exome AF: 0.0317

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000217

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000354

Gnomad4 OTH exome AF: 0.00242

GnomAD4 genome AF: 0.00934 AC: 1422 AN: 152286 Hom.: 26 Cov.: 32 AF XY: 0.00892 AC XY: 664 AN XY: 74468

Gnomad4 AFR AF: 0.0327

Gnomad4 AMR AF: 0.00287

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.0699 Hom.: 2356

Bravo AF: 0.0102

ESP6500AA AF: 0.0260 AC: 113

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.00214 AC: 253

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.78	T;T
MetaRNN	Benign	0.0076	T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.14
Sift	Benign	0.11	T;D
Sift4G	Benign	0.17	T;T
Polyphen		0.96	P;.
Vest4		0.40
MVP		0.65
MPC		0.56
ClinPred		0.068	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.21
gMVP		0.67

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

LitVar

Other links and lift over

dbSNP: rs35423325; hg19: chr8-37620247;