Genetic Variant PI4KA:p.Pro2012Pro (chr22-20710746-G-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_058004.4(PI4KA):c.6036C>T(p.Pro2012Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000686 in 151,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00069 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PI4KA
NM_058004.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0770

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 22-20710746-G-A is Benign according to our data. Variant chr22-20710746-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 784557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-20710746-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000686 (104/151600) while in subpopulation NFE AF= 0.00107 (72/67430). AF 95% confidence interval is 0.000869. There are 0 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PI4KA	NM_058004.4 link	c.6036C>T	p.Pro2012Pro	synonymous_variant	Exon 52 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.6036C>T	p.Pro2012Pro	synonymous_variant	Exon 52 of 55	1	NM_058004.4	ENSP00000255882.6		P42356-1

Frequencies

GnomAD3 genomes

AF:

0.000687

AC:

104

AN:

151482

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00443

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00107

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00222

AC:

556

AN:

250464

Hom.:

AF XY:

0.00243

AC XY:

329

AN XY:

135420

show subpopulations

Gnomad AFR exome

AF:

0.000801

Gnomad AMR exome

AF:

0.000811

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00186

Gnomad FIN exome

AF:

0.00166

Gnomad NFE exome

AF:

0.00343

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00227

AC:

3307

AN:

1454324

Hom.:

Cov.:

AF XY:

0.00222

AC XY:

1608

AN XY:

723440

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.000628

Gnomad4 ASJ exome

AF:

0.000767

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000919

Gnomad4 FIN exome

AF:

0.000732

Gnomad4 NFE exome

AF:

0.00273

Gnomad4 OTH exome

AF:

0.00171

GnomAD4 genome

AF:

0.000686

AC:

104

AN:

151600

Hom.:

Cov.:

AF XY:

0.000715

AC XY:

AN XY:

74176

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00107

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00420

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PI4KA: BP4, BP7 -

Dec 19, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

9.5

DANN

Benign

0.61

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

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