chr21-43743730-C-T

Variant names:

• chr21-43743730-C-T
• rs149442489
• NM_003681.5:c.254C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_003681.5(PDXK):​c.254C>T​(p.Thr85Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000826 in 1,610,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T85T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: PDXK NM_003681.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.06
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• neuropathy, hereditary motor and sensory, type VIc, with optic atrophy

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36479244).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003681.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDXK	NM_003681.5	MANE Select	c.254C>T	p.Thr85Met	missense	Exon 4 of 11	NP_003672.1	O00764-1
	PDXK	NM_001331030.2		c.134C>T	p.Thr45Met	missense	Exon 3 of 10	NP_001317959.1	F2Z2Y4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDXK	ENST00000291565.9	TSL:1 MANE Select	c.254C>T	p.Thr85Met	missense	Exon 4 of 11	ENSP00000291565.4	O00764-1
	PDXK	ENST00000468090.5	TSL:1	c.247+1959C>T		intron	N/A	ENSP00000418359.1	O00764-2
	PDXK	ENST00000343528.10	TSL:1	n.224C>T		non_coding_transcript_exon	Exon 3 of 10

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152074 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000960 AC: 24 AN: 250120 AF XY: 0.0000516

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000788 AC: 115 AN: 1458544 Hom.: 0 Cov.: 31 AF XY: 0.0000716 AC XY: 52 AN XY: 725808

African (AFR) AF: 0.0000898 AC: 3 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39678

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86170

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53352

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000866 AC: 96 AN: 1109070

Other (OTH) AF: 0.000133 AC: 8 AN: 60276

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152074 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74276

African (AFR) AF: 0.0000725 AC: 3 AN: 41392

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000170 Hom.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000742 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	0.95	L
PhyloP100		2.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.035	D
Polyphen		1.0	D
Vest4		0.33
MVP		0.73
MPC		0.83
ClinPred		0.044	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.46
gMVP		0.57
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs149442489; hg19: chr21-45163611;