22-20709921-TTGTC-T

Position:

• chr22-20709921-TTGTC-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The ENST00000255882.11(PI4KA):​c.6156_6159del​(p.Thr2053SerfsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PI4KA ENST00000255882.11 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.76

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 22-20709921-TTGTC-T is Pathogenic according to our data. Variant chr22-20709921-TTGTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 1325874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PI4KA	NM_058004.4	c.6156_6159del	p.Thr2053SerfsTer4	frameshift_variant	53/55	ENST00000255882.11	NP_477352.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PI4KA	ENST00000255882.11	c.6156_6159del	p.Thr2053SerfsTer4	frameshift_variant	53/55	1	NM_058004.4	ENSP00000255882	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 19 AN: 151192 Hom.: 0 Cov.: 29 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.000481

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000281 AC: 41 AN: 1457260 Hom.: 0 AF XY: 0.0000303 AC XY: 22 AN XY: 725300

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000813

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000280

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000132 AC: 20 AN: 151288 Hom.: 0 Cov.: 29 AF XY: 0.000203 AC XY: 15 AN XY: 73846

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000263

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000163

Gnomad4 OTH AF: 0.000477

Alfa AF: 0.00245 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia 84, autosomal recessive Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	Apr 27, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 28, 2022	- -

Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 28, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 29, 2022

This sequence change creates a premature translational stop signal (p.Thr2053Serfs*4) in the PI4KA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PI4KA are known to be pathogenic (PMID: 34415322). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with PI4KA-related condition (PMID: 34415322). ClinVar contains an entry for this variant (Variation ID: 1325874). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139598272; hg19: chr22-21064209;