22-20709769-C-T

Variant names:

• chr22-20709769-C-T
• rs28718601
• NM_058004.4:c.6173+139G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_058004.4(PI4KA):​c.6173+139G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0703 in 417,084 control chromosomes in the GnomAD database, including 7,178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.033 (35 hom., cov: 20)
  • Exomes 𝑓: 0.080 (7143 hom.)
• Consequence: PI4KA NM_058004.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.13
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 22-20709769-C-T is Benign according to our data. Variant chr22-20709769-C-T is described in ClinVar as Benign. ClinVar VariationId is 1266351.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058004.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PI4KA	NM_058004.4	MANE Select	c.6173+139G>A		intron	N/A	NP_477352.3	P42356-1
	PI4KA	NM_001362863.2		c.6107+139G>A		intron	N/A	NP_001349792.1
	PI4KA	NM_001362862.2		c.6080+139G>A		intron	N/A	NP_001349791.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PI4KA	ENST00000255882.11	TSL:1 MANE Select	c.6173+139G>A		intron	N/A	ENSP00000255882.6	P42356-1
	PI4KA	ENST00000477245.5	TSL:1	n.2546+139G>A		intron	N/A
	PI4KA	ENST00000939414.1		c.6209+139G>A		intron	N/A	ENSP00000609473.1

Frequencies

GnomAD3 genomes AF: 0.0331 AC: 2763 AN: 83422 Hom.: 34 Cov.: 20

Gnomad AFR AF: 0.0364

Gnomad AMI AF: 0.0423

Gnomad AMR AF: 0.0316

Gnomad ASJ AF: 0.0272

Gnomad EAS AF: 0.0218

Gnomad SAS AF: 0.0132

Gnomad FIN AF: 0.0215

Gnomad MID AF: 0.0313

Gnomad NFE AF: 0.0362

Gnomad OTH AF: 0.0475

GnomAD4 exome AF: 0.0796 AC: 26551 AN: 333624 Hom.: 7143 AF XY: 0.0759 AC XY: 13698 AN XY: 180482

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.159 AC: 1156 AN: 7250

American (AMR) AF: 0.190 AC: 3215 AN: 16942

Ashkenazi Jewish (ASJ) AF: 0.0842 AC: 800 AN: 9504

East Asian (EAS) AF: 0.0823 AC: 1294 AN: 15730

South Asian (SAS) AF: 0.0597 AC: 2451 AN: 41032

European-Finnish (FIN) AF: 0.0374 AC: 1261 AN: 33754

Middle Eastern (MID) AF: 0.0622 AC: 91 AN: 1462

European-Non Finnish (NFE) AF: 0.0777 AC: 14839 AN: 190862

Other (OTH) AF: 0.0845 AC: 1444 AN: 17088

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0332 AC: 2769 AN: 83460 Hom.: 35 Cov.: 20 AF XY: 0.0342 AC XY: 1399 AN XY: 40954

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0365 AC: 683 AN: 18726

American (AMR) AF: 0.0316 AC: 243 AN: 7682

Ashkenazi Jewish (ASJ) AF: 0.0272 AC: 52 AN: 1912

East Asian (EAS) AF: 0.0221 AC: 61 AN: 2754

South Asian (SAS) AF: 0.0135 AC: 42 AN: 3108

European-Finnish (FIN) AF: 0.0215 AC: 160 AN: 7428

Middle Eastern (MID) AF: 0.0349 AC: 6 AN: 172

European-Non Finnish (NFE) AF: 0.0362 AC: 1454 AN: 40190

Other (OTH) AF: 0.0470 AC: 51 AN: 1086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.306 Hom.: 760

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.26
DANN	Benign	0.64
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28718601; hg19: chr22-21064057; COSMIC: COSV55421443; COSMIC: COSV55421443;