21-43752747-G-T

Variant names:

• chr21-43752747-G-T
• rs2010795
• NM_003681.5:c.622+118G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003681.5(PDXK):​c.622+118G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 488,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: PDXK NM_003681.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.91
• Publications: 0 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDXK	NM_003681.5	c.622+118G>T		intron_variant	Intron 8 of 10	ENST00000291565.9	NP_003672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDXK	ENST00000291565.9	c.622+118G>T		intron_variant	Intron 8 of 10	1	NM_003681.5	ENSP00000291565.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 1 AN: 488186 Hom.: 0 AF XY: 0.00000388 AC XY: 1 AN XY: 258062

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

African (AFR) AF: 0.00 AC: 0 AN: 14084

American (AMR) AF: 0.00 AC: 0 AN: 26966

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15544

East Asian (EAS) AF: 0.00 AC: 0 AN: 30390

South Asian (SAS) AF: 0.0000197 AC: 1 AN: 50646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30964

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3350

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 288686

Other (OTH) AF: 0.00 AC: 0 AN: 27556

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.93
DANN	Benign	0.58
PhyloP100		1.9

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

Other links and lift over

dbSNP: rs2010795; hg19: chr21-45172628;