chr22-20786992-CTT-C

Position:

• chr22-20786992-CTT-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The ENST00000215727.10(SERPIND1):​c.1429_1430del​(p.Phe477ProfsTer28) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPIND1 ENST00000215727.10 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.83

Genes affected

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0487 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-20786992-CTT-C is Pathogenic according to our data. Variant chr22-20786992-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 14954.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPIND1	NM_000185.4	c.1429_1430del	p.Phe477ProfsTer28	frameshift_variant	5/5	ENST00000215727.10	NP_000176.2
PI4KA	NM_058004.4	c.2328+6199_2328+6200del		intron_variant		ENST00000255882.11	NP_477352.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPIND1	ENST00000215727.10	c.1429_1430del	p.Phe477ProfsTer28	frameshift_variant	5/5	1	NM_000185.4	ENSP00000215727	P1
PI4KA	ENST00000255882.11	c.2328+6199_2328+6200del		intron_variant		1	NM_058004.4	ENSP00000255882	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Heparin cofactor II deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

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: rs587777760; hg19: chr22-21141280;