21-43741749-T-A

Position:

• chr21-43741749-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_003681.5(PDXK):​c.225T>A​(p.Asn75Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PDXK NM_003681.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -0.181

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-43741749-T-A is Pathogenic according to our data. Variant chr21-43741749-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 812519.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDXK	NM_003681.5	c.225T>A	p.Asn75Lys	missense_variant	3/11	ENST00000291565.9	NP_003672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDXK	ENST00000291565.9	c.225T>A	p.Asn75Lys	missense_variant	3/11	1	NM_003681.5	ENSP00000291565.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Neuropathy, hereditary motor and sensory, type VIc, with optic atrophy Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 20, 2024	- -
Likely pathogenic, criteria provided, single submitter	research	Institute of Human Genetics, Cologne University	Sep 30, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	8.6
DANN	Benign	0.83
DEOGEN2	Benign	0.35	.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.2	L;L;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Uncertain	0.37
Sift	Benign	0.60	T;T;T
Sift4G	Benign	0.73	T;T;T
Polyphen		0.030	B;D;.
Vest4		0.76
MutPred		0.52		Gain of catalytic residue at N75 (P = 0.0237);Gain of catalytic residue at N75 (P = 0.0237);.;
MVP		0.74
MPC		1.5
ClinPred		0.79	D
GERP RS		-6.5
Varity_R		0.65
gMVP		0.40

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: rs1601814238; hg19: chr21-45161630;