22-20709921-TTGTC-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_058004.4(PI4KA):c.6156_6159delGACA(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
NM_058004.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.76

Variant links:

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]

PI4KA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 rank	MANE	Protein	UniProt
PI4KA	NM_058004.4 link	c.6156_6159delGACA	p.Thr2053SerfsTer4	frameshift_variant	Exon 53 of 55	ENST00000255882.11	NP_477352.3	P42356-1Q4LE69B4DYG5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PI4KA	ENST00000255882.11 link	c.6156_6159delGACA	p.Thr2053SerfsTer4	frameshift_variant	Exon 53 of 55	1	NM_058004.4	ENSP00000255882.6		P42356-1

Frequencies

GnomAD3 genomes

AF:

0.000126

AC:

AN:

151192

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0000603

AC:

AN:

248632

AF XY:

0.0000520

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000582

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000116

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000281

AC:

AN:

1457260

Hom.:

AF XY:

0.0000303

AC XY:

AN XY:

725300

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33354

Gnomad4 AMR exome

AF:

0.0000224

AC:

AN:

44708

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26098

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39668

Gnomad4 SAS exome

AF:

0.0000813

AC:

AN:

86130

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53394

Gnomad4 NFE exome

AF:

0.0000280

AC:

AN:

1107928

Gnomad4 Remaining exome

AF:

0.0000332

AC:

AN:

60232

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000132

AC:

AN:

151288

Hom.:

Cov.:

AF XY:

0.000203

AC XY:

AN XY:

73846

show subpopulations

Gnomad4 AFR

AF:

0.0000242

AC:

0.0000242131

AN:

0.0000242131

Gnomad4 AMR

AF:

0.000263

AC:

0.000262778

AN:

0.000262778

Gnomad4 ASJ

AF:

0.000289

AC:

0.000289352

AN:

0.000289352

Gnomad4 EAS

AF:

0.000195

AC:

0.000194553

AN:

0.000194553

Gnomad4 SAS

AF:

0.000209

AC:

0.000209293

AN:

0.000209293

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000163

AC:

0.000162891

AN:

0.000162891

Gnomad4 OTH

AF:

0.000477

AC:

0.000477099

AN:

0.000477099

⚠️ The allele balance in gnomAD4 Genomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00245

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spastic paraplegia 84, autosomal recessive

Pathogenic:2

Apr 27, 2023

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Sep 28, 2022

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis

Pathogenic:1

Sep 28, 2022

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Aug 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=4/196

disease causing (fs/PTC)

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over