Genetic Variant NM_006218.4:c.-77+8483C>T (chr3-179157086-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006218.4(PIK3CA):c.-77+8483C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 152,034 control chromosomes in the GnomAD database, including 5,815 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.25 ( 5815 hom., cov: 32)

Consequence

PIK3CA
NM_006218.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.781

Publications

20 publications found

Variant links:

Genes affected

PIK3CA (HGNC:8975): (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) Phosphatidylinositol 3-kinase is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate PtdIns, PtdIns4P and PtdIns(4,5)P2. This gene has been found to be oncogenic and has been implicated in cervical cancers. A pseudogene of this gene has been defined on chromosome 22. [provided by RefSeq, Apr 2016]

PIK3CA Gene-Disease associations (from GenCC):

overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
megalencephaly-capillary malformation-polymicrogyria syndrome
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
vascular malformation
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
Cowden disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Cowden syndrome 5
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PIK3CA links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CA	NM_006218.4 link	c.-77+8483C>T		intron_variant	Intron 1 of 20	ENST00000263967.4	NP_006209.2	P42336Q4LE51
PIK3CA	XM_006713658.5 link	c.-77+8867C>T		intron_variant	Intron 1 of 20		XP_006713721.1	P42336Q4LE51

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4 link	c.-77+8483C>T		intron_variant	Intron 1 of 20	2	NM_006218.4	ENSP00000263967.3		P42336

Frequencies

GnomAD3 genomes

AF:

0.252

AC:

38242

AN:

151916

Hom.:

5805

Cov.:

show subpopulations

Gnomad AFR

AF:

0.421

Gnomad AMI

AF:

0.299

Gnomad AMR

AF:

0.226

Gnomad ASJ

AF:

0.249

Gnomad EAS

AF:

0.102

Gnomad SAS

AF:

0.242

Gnomad FIN

AF:

0.160

Gnomad MID

AF:

0.311

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.253

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.252

AC:

38295

AN:

152034

Hom.:

5815

Cov.:

AF XY:

0.250

AC XY:

18575

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.421

AC:

17464

AN:

41440

American (AMR)

AF:

0.227

AC:

3464

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.249

AC:

864

AN:

3466

East Asian (EAS)

AF:

0.102

AC:

527

AN:

5182

South Asian (SAS)

AF:

0.241

AC:

1161

AN:

4822

European-Finnish (FIN)

AF:

0.160

AC:

1690

AN:

10580

Middle Eastern (MID)

AF:

0.317

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.180

AC:

12235

AN:

67958

Other (OTH)

AF:

0.250

AC:

528

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1357

2714

4070

5427

6784

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.205

Hom.:

1830

Bravo

AF:

0.267

Asia WGS

AF:

0.183

AC:

637

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.28

(source)

DANN

Benign

0.71

PhyloP100

-0.78

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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NM_006218.4:c.-77+8483C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over