rs3729679

Variant names:

• chr3-179204642-A-G
• rs3729679
• NM_006218.4:c.1145+54A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006218.4(PIK3CA):​c.1145+54A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 824,144 control chromosomes in the GnomAD database, including 115,968 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (26129 hom., cov: 30)
  • Exomes 𝑓: 0.51 (89839 hom.)
• Consequence: PIK3CA NM_006218.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.26
• Publications: 17 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-179204642-A-G is Benign according to our data. Variant chr3-179204642-A-G is described in ClinVar as Benign. ClinVar VariationId is 1236289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.1145+54A>G		intron_variant	Intron 6 of 20	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.1145+54A>G		intron_variant	Intron 6 of 20		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.1145+54A>G		intron_variant	Intron 6 of 20	2	NM_006218.4	ENSP00000263967.3

Frequencies

GnomAD3 genomes AF: 0.573 AC: 86887 AN: 151762 Hom.: 26093 Cov.: 30

Gnomad AFR AF: 0.756

Gnomad AMI AF: 0.747

Gnomad AMR AF: 0.510

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.468

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.589

GnomAD4 exome AF: 0.505 AC: 339709 AN: 672264 Hom.: 89839 AF XY: 0.505 AC XY: 179483 AN XY: 355440

African (AFR) AF: 0.765 AC: 13603 AN: 17790

American (AMR) AF: 0.473 AC: 18074 AN: 38204

Ashkenazi Jewish (ASJ) AF: 0.578 AC: 11009 AN: 19062

East Asian (EAS) AF: 0.206 AC: 7162 AN: 34840

South Asian (SAS) AF: 0.476 AC: 29200 AN: 61296

European-Finnish (FIN) AF: 0.441 AC: 22185 AN: 50256

Middle Eastern (MID) AF: 0.619 AC: 2170 AN: 3504

European-Non Finnish (NFE) AF: 0.529 AC: 219167 AN: 414566

Other (OTH) AF: 0.523 AC: 17139 AN: 32746

GnomAD4 genome AF: 0.573 AC: 86980 AN: 151880 Hom.: 26129 Cov.: 30 AF XY: 0.563 AC XY: 41777 AN XY: 74196

African (AFR) AF: 0.756 AC: 31323 AN: 41424

American (AMR) AF: 0.511 AC: 7793 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 1980 AN: 3466

East Asian (EAS) AF: 0.222 AC: 1150 AN: 5170

South Asian (SAS) AF: 0.468 AC: 2255 AN: 4816

European-Finnish (FIN) AF: 0.433 AC: 4556 AN: 10512

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.527 AC: 35817 AN: 67926

Other (OTH) AF: 0.586 AC: 1231 AN: 2102

Alfa AF: 0.566 Hom.: 3812

Bravo AF: 0.589

Asia WGS AF: 0.357 AC: 1242 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.32
DANN	Benign	0.74
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs3729679; hg19: chr3-178922430; COSMIC: COSV55874940;