rs426917

Variant names:

• chr22-20709384-G-A
• rs426917
• NM_058004.4:c.6174-5C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-20709384-G-A
• chr22-20709384-G-C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_058004.4(PI4KA):​c.6174-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (5898 hom., cov: 20)
  • Exomes 𝑓: 0.087 (30130 hom.)
  • Failed GnomAD Quality Control
• Consequence: PI4KA NM_058004.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001908
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.343
• Publications: 0 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 22-20709384-G-A is Benign according to our data. Variant chr22-20709384-G-A is described in ClinVar as Benign. ClinVar VariationId is 769146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5898 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.6174-5C>T		splice_region intron	N/A	NP_477352.3	P42356-1
	PI4KA	NM_001362863.2		c.6108-5C>T		splice_region intron	N/A	NP_001349792.1
	PI4KA	NM_001362862.2		c.6081-5C>T		splice_region 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.6174-5C>T		splice_region intron	N/A	ENSP00000255882.6	P42356-1
	PI4KA	ENST00000477245.5	TSL:1	n.2547-5C>T		splice_region intron	N/A
	PI4KA	ENST00000939412.1		c.6181C>T	p.Pro2061Ser	missense	Exon 54 of 55	ENSP00000609471.1

Frequencies

GnomAD3 genomes AF: 0.324 AC: 30661 AN: 94714 Hom.: 5885 Cov.: 20

Gnomad AFR AF: 0.382

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.337

GnomAD2 exomes AF: 0.0869 AC: 15500 AN: 178280 AF XY: 0.0789

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.164

Gnomad ASJ exome AF: 0.0542

Gnomad EAS exome AF: 0.194

Gnomad FIN exome AF: 0.00515

Gnomad NFE exome AF: 0.0655

Gnomad OTH exome AF: 0.129

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0871 AC: 90245 AN: 1036382 Hom.: 30130 Cov.: 24 AF XY: 0.0904 AC XY: 46643 AN XY: 516052

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

African (AFR) AF: 0.177 AC: 3605 AN: 20374

American (AMR) AF: 0.211 AC: 5846 AN: 27672

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 3024 AN: 17330

East Asian (EAS) AF: 0.304 AC: 7084 AN: 23314

South Asian (SAS) AF: 0.134 AC: 8337 AN: 62120

European-Finnish (FIN) AF: 0.0766 AC: 3180 AN: 41510

Middle Eastern (MID) AF: 0.138 AC: 385 AN: 2782

European-Non Finnish (NFE) AF: 0.0668 AC: 53450 AN: 799826

Other (OTH) AF: 0.129 AC: 5334 AN: 41454

⚠️ 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: 0.324 AC: 30704 AN: 94804 Hom.: 5898 Cov.: 20 AF XY: 0.311 AC XY: 14281 AN XY: 45958

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

African (AFR) AF: 0.383 AC: 8748 AN: 22860

American (AMR) AF: 0.362 AC: 3137 AN: 8674

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 825 AN: 2308

East Asian (EAS) AF: 0.352 AC: 999 AN: 2840

South Asian (SAS) AF: 0.232 AC: 720 AN: 3110

European-Finnish (FIN) AF: 0.161 AC: 1262 AN: 7860

Middle Eastern (MID) AF: 0.300 AC: 51 AN: 170

European-Non Finnish (NFE) AF: 0.317 AC: 14346 AN: 45232

Other (OTH) AF: 0.336 AC: 425 AN: 1266

⚠️ 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: 0.250 Hom.: 675

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.1
DANN	Benign	0.75
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
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

Other links and lift over

dbSNP: rs426917; hg19: chr22-21063672; COSMIC: COSV55405412; COSMIC: COSV55405412;