5-68293728-A-T

Variant names:

• chr5-68293728-A-T
• rs3730091
• NM_181523.3:c.1319A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_181523.3(PIK3R1):​c.1319A>T​(p.Asp440Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000755 in 1,324,144 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D440G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: PIK3R1 NM_181523.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.95
• Publications: 21 publications found

Genes affected

PIK3R1 (HGNC:8979): (phosphoinositide-3-kinase regulatory subunit 1) Phosphatidylinositol 3-kinase phosphorylates the inositol ring of phosphatidylinositol at the 3-prime position. The enzyme comprises a 110 kD catalytic subunit and a regulatory subunit of either 85, 55, or 50 kD. This gene encodes the 85 kD regulatory subunit. Phosphatidylinositol 3-kinase plays an important role in the metabolic actions of insulin, and a mutation in this gene has been associated with insulin resistance. Alternative splicing of this gene results in four transcript variants encoding different isoforms. [provided by RefSeq, Jun 2011]

PIK3R1 Gene-Disease associations (from GenCC):

• immunodeficiency 36 with lymphoproliferation

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• SHORT syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• agammaglobulinemia 7, autosomal recessive

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• activated PI3K-delta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal agammaglobulinemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181523.3. 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
	PIK3R1	NM_181523.3	MANE Select	c.1319A>T	p.Asp440Val	missense	Exon 11 of 16	NP_852664.1
	PIK3R1	NM_181504.4		c.509A>T	p.Asp170Val	missense	Exon 5 of 10	NP_852556.2
	PIK3R1	NM_181524.2		c.419A>T	p.Asp140Val	missense	Exon 5 of 10	NP_852665.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R1	ENST00000521381.6	TSL:1 MANE Select	c.1319A>T	p.Asp440Val	missense	Exon 11 of 16	ENSP00000428056.1
	PIK3R1	ENST00000336483.10	TSL:1	c.509A>T	p.Asp170Val	missense	Exon 5 of 10	ENSP00000338554.5
	PIK3R1	ENST00000320694.13	TSL:1	c.419A>T	p.Asp140Val	missense	Exon 5 of 10	ENSP00000323512.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000435 AC: 1 AN: 229834 AF XY: 0.00

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: 0.00000922

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.55e-7 AC: 1 AN: 1324144 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 664188

African (AFR) AF: 0.00 AC: 0 AN: 29810

American (AMR) AF: 0.00 AC: 0 AN: 36998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24608

East Asian (EAS) AF: 0.00 AC: 0 AN: 38838

South Asian (SAS) AF: 0.00 AC: 0 AN: 78080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5446

European-Non Finnish (NFE) AF: 9.98e-7 AC: 1 AN: 1001546

Other (OTH) AF: 0.00 AC: 0 AN: 55606

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.065	D
MutationAssessor	Benign	1.8	L
PhyloP100		8.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.010	D
Sift4G	Benign	0.10	T
Polyphen		0.88	P
Vest4		0.66
MutPred		0.43		Loss of ubiquitination at K438 (P = 0.0413)
MVP		0.98
MPC		1.8
ClinPred		0.93	D
GERP RS		5.1
Varity_R		0.75
gMVP		0.89
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs3730091; hg19: chr5-67589556;