Genetic Variant PDXK:c.143-100C>A (chr21-43741567-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001331030.2(PDXK):c.17C>A(p.Pro6Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,395,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. 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. P6L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

PDXK
NM_001331030.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.761

Variant links:

Genes affected

PDXK (HGNC:8819): (pyridoxal kinase) The protein encoded by this gene phosphorylates vitamin B6, a step required for the conversion of vitamin B6 to pyridoxal-5-phosphate, an important cofactor in intermediary metabolism. The encoded protein is cytoplasmic and probably acts as a homodimer. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

PDXK links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12102318).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDXK	NM_003681.5 link	c.143-100C>A		intron_variant	Intron 2 of 10	ENST00000291565.9	NP_003672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDXK	ENST00000291565.9 link	c.143-100C>A		intron_variant	Intron 2 of 10	1	NM_003681.5	ENSP00000291565.4		O00764-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.17e-7

AC:

AN:

1395020

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689266

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31330

American (AMR)

AF:

0.00

AC:

AN:

32460

Ashkenazi Jewish (ASJ)

AF:

0.0000444

AC:

AN:

22532

East Asian (EAS)

AF:

0.00

AC:

AN:

38578

South Asian (SAS)

AF:

0.00

AC:

AN:

77448

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49826

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4460

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1080824

Other (OTH)

AF:

0.00

AC:

AN:

57562

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.53

CADD

Benign

2.2

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.048

Eigen

Benign

-0.83

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.41

M_CAP

Benign

0.0034

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.97

PhyloP100

-0.76

PROVEAN

Benign

1.7

REVEL

Benign

0.038

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Vest4

0.22

MutPred

0.43

Gain of MoRF binding (P = 0.0066);

MVP

0.043

ClinPred

0.094

GERP RS

-0.46

PromoterAI

0.052

Neutral

(source)

Mutation Taster

=95/5

polymorphism

(source)

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

Below is the list of publications found by LitVar for variant 21:43741567 C>A . It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over