Variant chr22-20710808-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP2PP3PP5_Very_Strong

The NM_058004.4(PI4KA):c.5974C>T(p.Pro1992Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

PI4KA
NM_058004.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 9.65

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a domain PI3K/PI4K catalytic (size 278) in uniprot entity PI4KA_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_058004.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PI4KA. . Gene score misZ 3.5271 (greater than the threshold 3.09). Trascript score misZ 4.6291 (greater than threshold 3.09). GenCC has associacion of gene with polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.783

PP5

Variant 22-20710808-G-A is Pathogenic according to our data. Variant chr22-20710808-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1675874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PI4KA	NM_058004.4 linkuse as main transcript	c.5974C>T	p.Pro1992Ser	missense_variant	52/55	ENST00000255882.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PI4KA	ENST00000255882.11 linkuse as main transcript	c.5974C>T	p.Pro1992Ser	missense_variant	52/55	1	NM_058004.4	P1	P42356-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Sep 16, 2022

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Benign

0.021

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-7.6

.;D

REVEL

Uncertain

0.41

Sift

Benign

0.10

.;T

Sift4G

Benign

0.068

T;T

Polyphen

0.97

.;D

Vest4

0.84

MVP

0.57

MPC

2.5

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.48

gMVP

0.79

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over