3-130679392-C-T

Variant names:

• chr3-130679392-C-T
• NM_014602.3:c.4000G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014602.3(PIK3R4):​c.4000G>A​(p.Asp1334Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PIK3R4 NM_014602.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.38
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014602.3. 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
	PIK3R4	NM_014602.3	MANE Select	c.4000G>A	p.Asp1334Asn	missense	Exon 20 of 20	NP_055417.1	Q99570

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R4	ENST00000356763.8	TSL:1 MANE Select	c.4000G>A	p.Asp1334Asn	missense	Exon 20 of 20	ENSP00000349205.3	Q99570
	PIK3R4	ENST00000954554.1		c.4006G>A	p.Asp1336Asn	missense	Exon 20 of 20	ENSP00000624613.1
	PIK3R4	ENST00000893860.1		c.3991G>A	p.Asp1331Asn	missense	Exon 20 of 20	ENSP00000563919.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460642 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726752

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110958

Other (OTH) AF: 0.00 AC: 0 AN: 60340

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.4
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.035	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.61		Loss of catalytic residue at D1334 (P = 0.0222)
MVP		0.69
MPC		0.87
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.48
gMVP		0.55
Mutation Taster		=61/39	polymorphism

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

hg19: chr3-130398236;