5-112788672-T-C

Variant names:

• chr5-112788672-T-C
• rs2431238
• NM_000038.6:c.646-3774T>C

Variant summary

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

The NM_000038.6(APC):​c.646-3774T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.681 in 152,000 control chromosomes in the GnomAD database, including 35,585 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars).

• Frequency: Genomes: 𝑓 0.68 (35585 hom., cov: 32)
• Consequence: APC NM_000038.6 intron
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: -0.265
• Publications: 21 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.88 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.646-3774T>C		intron_variant	Intron 6 of 15	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.646-3774T>C		intron_variant	Intron 6 of 15	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes AF: 0.681 AC: 103370 AN: 151882 Hom.: 35555 Cov.: 32

Gnomad AFR AF: 0.710

Gnomad AMI AF: 0.633

Gnomad AMR AF: 0.718

Gnomad ASJ AF: 0.617

Gnomad EAS AF: 0.902

Gnomad SAS AF: 0.754

Gnomad FIN AF: 0.556

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.655

Gnomad OTH AF: 0.682

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

GnomAD4 genome AF: 0.681 AC: 103454 AN: 152000 Hom.: 35585 Cov.: 32 AF XY: 0.680 AC XY: 50527 AN XY: 74294

African (AFR) AF: 0.710 AC: 29454 AN: 41456

American (AMR) AF: 0.718 AC: 10959 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.617 AC: 2140 AN: 3470

East Asian (EAS) AF: 0.902 AC: 4677 AN: 5186

South Asian (SAS) AF: 0.753 AC: 3629 AN: 4820

European-Finnish (FIN) AF: 0.556 AC: 5864 AN: 10556

Middle Eastern (MID) AF: 0.687 AC: 202 AN: 294

European-Non Finnish (NFE) AF: 0.655 AC: 44522 AN: 67930

Other (OTH) AF: 0.678 AC: 1431 AN: 2110

Alfa AF: 0.669 Hom.: 25219

Bravo AF: 0.697

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial colorectal cancer Other:1

-

Systems Biology Platform Zhejiang California International NanoSystems Institute

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.2
DANN	Benign	0.64
PhyloP100		-0.27
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: rs2431238; hg19: chr5-112124369;