chr3-179210203-A-T

Variant names:

• chr3-179210203-A-T
• rs761246978
• NM_006218.4:c.1269A>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006218.4(PIK3CA):​c.1269A>T​(p.Ala423Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000628 in 1,433,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: PIK3CA NM_006218.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.239
• Publications: 0 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 3-179210203-A-T is Benign according to our data. Variant chr3-179210203-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 526642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.239 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 9 AD gene.

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.1269A>T	p.Ala423Ala	synonymous	Exon 8 of 21	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.1269A>T	p.Ala423Ala	synonymous	Exon 8 of 21	ENSP00000263967.3	P42336
	PIK3CA	ENST00000955190.1		c.1299A>T	p.Ala433Ala	synonymous	Exon 8 of 21	ENSP00000625249.1
	PIK3CA	ENST00000876545.1		c.1269A>T	p.Ala423Ala	synonymous	Exon 9 of 22	ENSP00000546604.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000449 AC: 1 AN: 222958 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000946

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000628 AC: 9 AN: 1433962 Hom.: 0 Cov.: 30 AF XY: 0.00000701 AC XY: 5 AN XY: 712942

African (AFR) AF: 0.00 AC: 0 AN: 31608

American (AMR) AF: 0.00 AC: 0 AN: 35582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39082

South Asian (SAS) AF: 0.00 AC: 0 AN: 79700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00000815 AC: 9 AN: 1104654

Other (OTH) AF: 0.00 AC: 0 AN: 59362

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cowden syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.3
DANN	Benign	0.55
PhyloP100		-0.24

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: rs761246978; hg19: chr3-178927991;