18-41955311-T-C

Position:

• chr18-41955311-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002647.4(PIK3C3):​c.20T>C​(p.Phe7Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F7V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3C3 NM_002647.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.80

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3C3	NM_002647.4	c.20T>C	p.Phe7Ser	missense_variant	1/25	ENST00000262039.9
PIK3C3	NM_001308020.2	c.20T>C	p.Phe7Ser	missense_variant	1/24
PIK3C3	XM_047437549.1	c.20T>C	p.Phe7Ser	missense_variant	1/22
PIK3C3	XM_047437551.1	c.20T>C	p.Phe7Ser	missense_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3C3	ENST00000262039.9	c.20T>C	p.Phe7Ser	missense_variant	1/25	1	NM_002647.4	P1
PIK3C3	ENST00000586545.5	c.20T>C	p.Phe7Ser	missense_variant	1/4	1
PIK3C3	ENST00000398870.7	c.20T>C	p.Phe7Ser	missense_variant	1/24	2
PIK3C3	ENST00000590220.1	n.50T>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The c.20T>C (p.F7S) alteration is located in exon 1 (coding exon 1) of the PIK3C3 gene. This alteration results from a T to C substitution at nucleotide position 20, causing the phenylalanine (F) at amino acid position 7 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.;T;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.88	D;D;T;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.2	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.9	D;.;D;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D;.;T;.
Sift4G	Pathogenic	0.0010	D;.;T;D
Polyphen		0.0060	B;.;B;.
Vest4		0.81
MutPred		0.72		Gain of disorder (P = 0.0277);Gain of disorder (P = 0.0277);Gain of disorder (P = 0.0277);Gain of disorder (P = 0.0277);
MVP		0.90
MPC		1.0
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.71

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-39535276;