3-58382548-A-G

Variant names:

• chr3-58382548-A-G
• rs751989239
• NM_017771.5:c.236A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017771.5(PXK):​c.236A>G​(p.Lys79Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000529 in 1,437,532 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: PXK NM_017771.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.68

Genes affected

PXK (HGNC:23326): (PX domain containing serine/threonine kinase like) This gene encodes a phox (PX) domain-containing protein which may be involved in synaptic transmission and the ligand-induced internalization and degradation of epidermal growth factors. Variations in this gene may be associated with susceptibility to systemic lupus erythematosus (SLE). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PXK	NM_017771.5	c.236A>G	p.Lys79Arg	missense_variant	Exon 4 of 18	ENST00000356151.7	NP_060241.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PXK	ENST00000356151.7	c.236A>G	p.Lys79Arg	missense_variant	Exon 4 of 18	1	NM_017771.5	ENSP00000348472.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000440 AC: 1 AN: 227020 Hom.: 0 AF XY: 0.00000812 AC XY: 1 AN XY: 123140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000940

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000529 AC: 76 AN: 1437532 Hom.: 0 Cov.: 35 AF XY: 0.0000560 AC XY: 40 AN XY: 714716

Gnomad4 AFR exome AF: 0.0000313

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000643

Gnomad4 OTH exome AF: 0.0000674

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000624 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.236A>G (p.K79R) alteration is located in exon 4 (coding exon 4) of the PXK gene. This alteration results from a A to G substitution at nucleotide position 236, causing the lysine (K) at amino acid position 79 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T;T;.;.;.;.;T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;.;D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.81	L;.;L;.;.;L;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.1	N;.;.;N;N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.28	T;.;.;T;T;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T
Polyphen		1.0	D;.;D;D;.;D;.;.
Vest4		0.55
MutPred		0.62		Loss of glycosylation at P77 (P = 0.0042);Loss of glycosylation at P77 (P = 0.0042);Loss of glycosylation at P77 (P = 0.0042);.;.;Loss of glycosylation at P77 (P = 0.0042);.;.;
MVP		0.75
MPC		0.52
ClinPred		0.84	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.20
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs751989239; hg19: chr3-58368275;