chr3-58390585-T-A

Variant names:

• chr3-58390585-T-A
• rs1363158507
• NM_017771.5:c.392T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001349525.2(PXK):​c.-20T>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,390 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PXK NM_001349525.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.26
• Publications: 0 publications found

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]

PXK Gene-Disease associations (from GenCC):

• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349525.2. 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
	PXK	NM_017771.5	MANE Select	c.392T>A	p.Ile131Asn	missense	Exon 5 of 18	NP_060241.2
	PXK	NM_001349525.2		c.-20T>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 16	NP_001336454.1
	PXK	NM_001289101.2		c.-20T>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 15	NP_001276030.1	Q7Z7A4-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PXK	ENST00000356151.7	TSL:1 MANE Select	c.392T>A	p.Ile131Asn	missense	Exon 5 of 18	ENSP00000348472.2	Q7Z7A4-1
	PXK	ENST00000302779.9	TSL:1	c.392T>A	p.Ile131Asn	missense	Exon 5 of 17	ENSP00000305045.6	W5RWE6
	PXK	ENST00000383716.7	TSL:1	c.392T>A	p.Ile131Asn	missense	Exon 5 of 19	ENSP00000373222.4	Q7Z7A4-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 250946 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460390 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726538

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44528

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111134

Other (OTH) AF: 0.00 AC: 0 AN: 60310

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0091	T
Eigen	Benign	0.029
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.16
Sift	Benign	0.19	T
Sift4G	Benign	0.28	T
Polyphen		0.0050	B
Vest4		0.82
MutPred		0.51		Gain of disorder (P = 0.0067)
MVP		0.44
MPC		0.47
ClinPred		0.51	D
GERP RS		5.9
Varity_R		0.32
gMVP		0.72
Mutation Taster		=40/60	disease causing

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

Other links and lift over

dbSNP: rs1363158507; hg19: chr3-58376312;