18-42004535-T-G

Variant names:

• chr18-42004535-T-G
• rs758711608
• NM_002647.4:c.1164T>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002647.4(PIK3C3):​c.1164T>G​(p.Asp388Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,586,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000077 (0 hom.)
• Consequence: PIK3C3 NM_002647.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04
• Publications: 0 publications found

Genes affected

PIK3C3 (HGNC:8974): (phosphatidylinositol 3-kinase catalytic subunit type 3) Enables 1-phosphatidylinositol-3-kinase activity. Involved in early endosome to late endosome transport and regulation of cytokinesis. Acts upstream of or within autophagy and protein lipidation. Located in autolysosome; late endosome; and midbody. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21599582).
• BS2: High AC in GnomAd4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002647.4. 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
	PIK3C3	NM_002647.4	MANE Select	c.1164T>G	p.Asp388Glu	missense	Exon 10 of 25	NP_002638.2
	PIK3C3	NM_001308020.2		c.975T>G	p.Asp325Glu	missense	Exon 9 of 24	NP_001294949.1	A8MYT4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3C3	ENST00000262039.9	TSL:1 MANE Select	c.1164T>G	p.Asp388Glu	missense	Exon 10 of 25	ENSP00000262039.3	Q8NEB9
	PIK3C3	ENST00000858068.1		c.1164T>G	p.Asp388Glu	missense	Exon 10 of 25	ENSP00000528127.1
	PIK3C3	ENST00000858070.1		c.1164T>G	p.Asp388Glu	missense	Exon 10 of 24	ENSP00000528129.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000134 AC: 3 AN: 223226 AF XY: 0.00000826

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000779

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000189

GnomAD4 exome AF: 0.00000767 AC: 11 AN: 1434866 Hom.: 0 Cov.: 31 AF XY: 0.00000561 AC XY: 4 AN XY: 713394

African (AFR) AF: 0.00 AC: 0 AN: 31566

American (AMR) AF: 0.0000281 AC: 1 AN: 35618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24506

East Asian (EAS) AF: 0.00 AC: 0 AN: 39552

South Asian (SAS) AF: 0.00 AC: 0 AN: 81278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5596

European-Non Finnish (NFE) AF: 0.00000634 AC: 7 AN: 1104516

Other (OTH) AF: 0.0000507 AC: 3 AN: 59196

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74302

African (AFR) AF: 0.0000966 AC: 4 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15262

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

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	Benign	0.20
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	-0.10
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.0
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.14
Sift	Benign	0.50	T
Sift4G	Benign	0.42	T
Polyphen		0.0050	B
Vest4		0.42
MutPred		0.58		Loss of stability (P = 0.1469)
MVP		0.57
MPC		0.19
ClinPred		0.19	T
GERP RS		5.5
Varity_R		0.26
gMVP		0.15
Mutation Taster		=77/23	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

dbSNP: rs758711608; hg19: chr18-39584499;