3-58410115-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_017771.5(PXK):c.1421A>T(p.Asn474Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00686 in 1,601,568 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0052 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (138 hom.)
• Consequence: PXK NM_017771.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.46

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034009814).
• BP6: Variant 3-58410115-A-T is Benign according to our data. Variant chr3-58410115-A-T is described in ClinVar as [Benign]. Clinvar id is 771351.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00519 (790/152254) while in subpopulation SAS AF= 0.0402 (194/4822). AF 95% confidence interval is 0.0356. There are 9 homozygotes in gnomad4. There are 405 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PXK	NM_017771.5	c.1421A>T	p.Asn474Ile	missense_variant	16/18	ENST00000356151.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PXK	ENST00000356151.7	c.1421A>T	p.Asn474Ile	missense_variant	16/18	1	NM_017771.5	P1

Frequencies

GnomAD3 genomes AF: 0.00523 AC: 796 AN: 152136 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0404

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.00550

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00929 AC: 2333 AN: 251154 Hom.: 38 AF XY: 0.0113 AC XY: 1540 AN XY: 135758

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00515

Gnomad ASJ exome AF: 0.0167

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0393

Gnomad FIN exome AF: 0.000837

Gnomad NFE exome AF: 0.00600

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.00703 AC: 10191 AN: 1449314 Hom.: 138 Cov.: 29 AF XY: 0.00831 AC XY: 6001 AN XY: 721874

Gnomad4 AFR exome AF: 0.000751

Gnomad4 AMR exome AF: 0.00481

Gnomad4 ASJ exome AF: 0.0152

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0404

Gnomad4 FIN exome AF: 0.00139

Gnomad4 NFE exome AF: 0.00476

Gnomad4 OTH exome AF: 0.00904

GnomAD4 genome AF: 0.00519 AC: 790 AN: 152254 Hom.: 9 Cov.: 32 AF XY: 0.00544 AC XY: 405 AN XY: 74450

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0402

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00548

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00604 Hom.: 4

Bravo AF: 0.00443

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00895 AC: 77

ExAC AF: 0.00997 AC: 1211

Asia WGS AF: 0.0150 AC: 52 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	22
Dann	Benign	0.97
DEOGEN2	Benign	0.0029	T;T;.;.;.;.;T;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.065
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;.;D;D;T
MetaRNN	Benign	0.0034	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;.;L;.;.;L;.;.;.
MutationTaster	Benign	0.98	N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.5	N;.;.;N;N;N;N;.;D
REVEL	Benign	0.10
Sift	Benign	0.19	T;.;.;T;T;T;D;.;.
Sift4G	Benign	0.33	T;T;T;T;T;T;T;T;D
Polyphen		0.0030	B;.;B;B;.;B;.;.;.
Vest4		0.39
MVP		0.53
MPC		0.34
ClinPred		0.024	T
GERP RS		4.8
Varity_R		0.084
gMVP		0.22

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: rs140203295; hg19: chr3-58395842; COSMIC: COSV99044117;