22-20781058-T-G

Variant names:

• chr22-20781058-T-G
• rs165862
• NM_058004.4:c.2328+12135A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_058004.4(PI4KA):​c.2328+12135A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 151,868 control chromosomes in the GnomAD database, including 20,681 homozygotes. 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: 𝑓 0.52 (20681 hom., cov: 31)
• Consequence: PI4KA NM_058004.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.00
• Publications: 18 publications found

Genes affected

PI4KA (HGNC:8983): (phosphatidylinositol 4-kinase alpha) This gene encodes a phosphatidylinositol (PI) 4-kinase which catalyzes the first committed step in the biosynthesis of phosphatidylinositol 4,5-bisphosphate. The mammalian PI 4-kinases have been classified into two types, II and III, based on their molecular mass, and modulation by detergent and adenosine. The protein encoded by this gene is a type III enzyme that is not inhibited by adenosine. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2018]

SERPIND1 (HGNC:4838): (serpin family D member 1) This gene belongs to the serpin gene superfamily. Serpins play roles in many processes including inflammation, blood clotting, and cancer metastasis. Members of this family have highly conserved secondary structures with a reactive center loop that interacts with the protease active site to inhibit protease activity. This gene encodes a plasma serine protease that functions as a thrombin and chymotrypsin inhibitor. The protein is activated by heparin, dermatan sulfate, and glycosaminoglycans. Allelic variations in this gene are associated with heparin cofactor II deficiency. [provided by RefSeq, Jul 2015]

SERPIND1 Gene-Disease associations (from GenCC):

• heparin cofactor 2 deficiency

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058004.4. 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
	PI4KA	NM_058004.4	MANE Select	c.2328+12135A>C		intron	N/A	NP_477352.3	P42356-1
	SERPIND1	NM_000185.4	MANE Select	c.889+857T>G		intron	N/A	NP_000176.2	P05546-1
	PI4KA	NM_001362863.2		c.2262+12135A>C		intron	N/A	NP_001349792.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PI4KA	ENST00000255882.11	TSL:1 MANE Select	c.2328+12135A>C		intron	N/A	ENSP00000255882.6	P42356-1
	SERPIND1	ENST00000215727.10	TSL:1 MANE Select	c.889+857T>G		intron	N/A	ENSP00000215727.5	P05546-1
	SERPIND1	ENST00000406799.1	TSL:1	c.889+857T>G		intron	N/A	ENSP00000384050.1	P05546-1

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78702 AN: 151752 Hom.: 20663 Cov.: 31

Gnomad AFR AF: 0.585

Gnomad AMI AF: 0.628

Gnomad AMR AF: 0.541

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.514

Gnomad SAS AF: 0.376

Gnomad FIN AF: 0.428

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.526

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.519 AC: 78775 AN: 151868 Hom.: 20681 Cov.: 31 AF XY: 0.513 AC XY: 38097 AN XY: 74194

African (AFR) AF: 0.584 AC: 24202 AN: 41416

American (AMR) AF: 0.542 AC: 8263 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 1540 AN: 3464

East Asian (EAS) AF: 0.514 AC: 2649 AN: 5154

South Asian (SAS) AF: 0.376 AC: 1805 AN: 4802

European-Finnish (FIN) AF: 0.428 AC: 4496 AN: 10514

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.501 AC: 34009 AN: 67948

Other (OTH) AF: 0.525 AC: 1106 AN: 2108

Alfa AF: 0.495 Hom.: 31391

Bravo AF: 0.533

Asia WGS AF: 0.447 AC: 1551 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.7
DANN	Benign	0.74
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs165862; hg19: chr22-21135346;