3-130690650-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014602.3(PIK3R4):c.3103A>G(p.Ile1035Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000699 in 1,585,496 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00081 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (9 hom.)
• Consequence: PIK3R4 NM_014602.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.35

Genes affected

PIK3R4 (HGNC:8982): (phosphoinositide-3-kinase regulatory subunit 4) Predicted to enable protein serine/threonine kinase activity. Involved in positive regulation of phosphatidylinositol 3-kinase activity; receptor catabolic process; and regulation of cytokinesis. Located in late endosome and microtubule cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072999597).
• BP6: Variant 3-130690650-T-C is Benign according to our data. Variant chr3-130690650-T-C is described in ClinVar as [Benign]. Clinvar id is 739849.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000814 (124/152260) while in subpopulation EAS AF= 0.0207 (107/5178). AF 95% confidence interval is 0.0175. There are 1 homozygotes in gnomad4. There are 68 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 123 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3R4	NM_014602.3	c.3103A>G	p.Ile1035Val	missense_variant	14/20	ENST00000356763.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3R4	ENST00000356763.8	c.3103A>G	p.Ile1035Val	missense_variant	14/20	1	NM_014602.3	P1
PIK3R4	ENST00000512677.1	n.8A>G		non_coding_transcript_exon_variant	1/6	3

Frequencies

GnomAD3 genomes AF: 0.000808 AC: 123 AN: 152142 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0204

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00161 AC: 386 AN: 239792 Hom.: 4 AF XY: 0.00154 AC XY: 199 AN XY: 129512

Gnomad AFR exome AF: 0.0000625

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0199

Gnomad SAS exome AF: 0.000429

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000163

Gnomad OTH exome AF: 0.000523

GnomAD4 exome AF: 0.000687 AC: 985 AN: 1433236 Hom.: 9 Cov.: 25 AF XY: 0.000669 AC XY: 477 AN XY: 713442

Gnomad4 AFR exome AF: 0.0000620

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0199

Gnomad4 SAS exome AF: 0.000459

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000105

Gnomad4 OTH exome AF: 0.000726

GnomAD4 genome AF: 0.000814 AC: 124 AN: 152260 Hom.: 1 Cov.: 32 AF XY: 0.000913 AC XY: 68 AN XY: 74462

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0207

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000943 Hom.: 2

Bravo AF: 0.00102

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00166 AC: 201

Asia WGS AF: 0.00779 AC: 28 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	15
Dann	Benign	0.97
DEOGEN2	Benign	0.058	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-1.1	N
MutationTaster	Benign	0.80	D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.088
Sift	Benign	0.16	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.17
MPC		0.20
ClinPred		0.016	T
GERP RS		3.9
Varity_R		0.037
gMVP		0.094

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

Other links and lift over

dbSNP: rs147350320; hg19: chr3-130409494; COSMIC: COSV63243132; COSMIC: COSV63243132;