ENST00000520401.1:n.229-6953A>G

Variant names:

• chr5-112822018-A-G
• rs863225312
• NM_000038.6:c.1408+27A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000038.6(APC):​c.1408+27A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000319 in 1,252,722 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: APC NM_000038.6 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.534
• Publications: 0 publications found

Genes affected

APC (HGNC:583): (APC regulator of WNT signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]

APC Gene-Disease associations (from GenCC):

• classic or attenuated familial adenomatous polyposis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• desmoid tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• familial adenomatous polyposis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• APC-related attenuated familial adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Turcot syndrome with polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 5-112822018-A-G is Benign according to our data. Variant chr5-112822018-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 217925.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000038.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	NM_000038.6	MANE Select	c.1408+27A>G		intron	N/A	NP_000029.2
	APC	NM_001407446.1		c.1438+27A>G		intron	N/A	NP_001394375.1
	APC	NM_001354896.2		c.1408+27A>G		intron	N/A	NP_001341825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000257430.9	TSL:5 MANE Select	c.1408+27A>G		intron	N/A	ENSP00000257430.4
	APC	ENST00000508376.6	TSL:1	c.1408+27A>G		intron	N/A	ENSP00000427089.2
	APC	ENST00000502371.3	TSL:1	n.1408+27A>G		intron	N/A	ENSP00000484935.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000319 AC: 4 AN: 1252722 Hom.: 0 Cov.: 18 AF XY: 0.00000158 AC XY: 1 AN XY: 633044

African (AFR) AF: 0.00 AC: 0 AN: 29466

American (AMR) AF: 0.00 AC: 0 AN: 43492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24800

East Asian (EAS) AF: 0.00 AC: 0 AN: 38532

South Asian (SAS) AF: 0.00 AC: 0 AN: 81232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5072

European-Non Finnish (NFE) AF: 0.00000324 AC: 3 AN: 925658

Other (OTH) AF: 0.0000187 AC: 1 AN: 53422

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.9
DANN	Benign	0.71
PhyloP100		0.53
PromoterAI		0.033	Neutral
Mutation Taster		=96/4	polymorphism

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: rs863225312; hg19: chr5-112157715;