3-179175241-A-G

Variant names:

• chr3-179175241-A-G
• rs7651265
• NM_006218.4:c.-76-23509A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006218.4(PIK3CA):​c.-76-23509A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 152,062 control chromosomes in the GnomAD database, including 1,228 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 0.13 (1228 hom., cov: 32)
• Consequence: PIK3CA NM_006218.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.163
• Publications: 28 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, 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)
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006218.4. 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
	PIK3CA	NM_006218.4	MANE Select	c.-76-23509A>G		intron	N/A	NP_006209.2	P42336

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CA	ENST00000263967.4	TSL:2 MANE Select	c.-76-23509A>G		intron	N/A	ENSP00000263967.3	P42336
	PIK3CA	ENST00000955190.1		c.-76-23509A>G		intron	N/A	ENSP00000625249.1
	PIK3CA	ENST00000876545.1		c.-76-23509A>G		intron	N/A	ENSP00000546604.1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19098 AN: 151946 Hom.: 1229 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.0984

Gnomad SAS AF: 0.0890

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.132

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

GnomAD4 genome AF: 0.126 AC: 19117 AN: 152062 Hom.: 1228 Cov.: 32 AF XY: 0.127 AC XY: 9431 AN XY: 74322

African (AFR) AF: 0.144 AC: 5990 AN: 41460

American (AMR) AF: 0.142 AC: 2165 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 428 AN: 3470

East Asian (EAS) AF: 0.0983 AC: 510 AN: 5190

South Asian (SAS) AF: 0.0887 AC: 428 AN: 4824

European-Finnish (FIN) AF: 0.142 AC: 1505 AN: 10568

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7619 AN: 67966

Other (OTH) AF: 0.130 AC: 273 AN: 2104

Alfa AF: 0.121 Hom.: 1328

Bravo AF: 0.129

Asia WGS AF: 0.0870 AC: 304 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.64
DANN	Benign	0.43
PhyloP100		-0.16
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: rs7651265; hg19: chr3-178893029;