NM_005026.5:c.780+3G>A

Variant names:

• chr1-9716622-G-A
• rs370943912
• NM_005026.5:c.780+3G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_005026.5(PIK3CD):​c.780+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,552,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: PIK3CD NM_005026.5 splice_region, intron
• Scores: Splicing: ADA: 0.00006622
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.54
• Publications: 0 publications found

Genes affected

PIK3CD (HGNC:8977): (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta) Phosphoinositide 3-kinases (PI3Ks) phosphorylate inositol lipids and are involved in the immune response. The protein encoded by this gene is a class I PI3K found primarily in leukocytes. Like other class I PI3Ks (p110-alpha p110-beta, and p110-gamma), the encoded protein binds p85 adapter proteins and GTP-bound RAS. However, unlike the other class I PI3Ks, this protein phosphorylates itself, not p85 protein.[provided by RefSeq, Jul 2010]

PIK3CD Gene-Disease associations (from GenCC):

• immunodeficiency 14

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• immunodeficiency 14b, autosomal recessive

  Inheritance: AR, Unknown Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• activated PI3K-delta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-9716622-G-A is Benign according to our data. Variant chr1-9716622-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 572074.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005026.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CD	NM_005026.5	MANE Select	c.780+3G>A		splice_region intron	N/A	NP_005017.3
	PIK3CD	NM_001437546.1		c.780+3G>A		splice_region intron	N/A	NP_001424475.1
	PIK3CD	NM_001350234.2		c.780+3G>A		splice_region intron	N/A	NP_001337163.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CD	ENST00000377346.9	TSL:1 MANE Select	c.780+3G>A		splice_region intron	N/A	ENSP00000366563.4
	PIK3CD	ENST00000361110.6	TSL:1	c.780+3G>A		splice_region intron	N/A	ENSP00000354410.2
	PIK3CD	ENST00000698711.1		n.1497G>A		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152258 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000101 AC: 16 AN: 159010 AF XY: 0.000166

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000242

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.000123 AC: 172 AN: 1399780 Hom.: 0 Cov.: 33 AF XY: 0.000142 AC XY: 98 AN XY: 691004

African (AFR) AF: 0.0000316 AC: 1 AN: 31616

American (AMR) AF: 0.0000557 AC: 2 AN: 35900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25208

East Asian (EAS) AF: 0.00 AC: 0 AN: 35816

South Asian (SAS) AF: 0.0000250 AC: 2 AN: 79978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48492

Middle Eastern (MID) AF: 0.000244 AC: 1 AN: 4094

European-Non Finnish (NFE) AF: 0.000144 AC: 156 AN: 1080748

Other (OTH) AF: 0.000173 AC: 10 AN: 57928

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152376 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74514

African (AFR) AF: 0.0000240 AC: 1 AN: 41590

American (AMR) AF: 0.000261 AC: 4 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68036

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000213 Hom.: 0

Bravo AF: 0.000147

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Immunodeficiency 14 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Benign	0.89
PhyloP100		2.5
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000066
dbscSNV1_RF	Benign	0.064
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: rs370943912; hg19: chr1-9776680;