5-112751630-T-G

Variant names:

• chr5-112751630-T-G
• rs11954856
• NM_000038.6:c.-18-3243T>G

Variant summary

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

The NM_000038.6(APC):​c.-18-3243T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 151,662 control chromosomes in the GnomAD database, including 22,957 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars).

• Frequency: Genomes: 𝑓 0.54 (22957 hom., cov: 32)
• Consequence: APC NM_000038.6 intron
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: -0.604
• Publications: 14 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.79 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.-18-3243T>G		intron_variant	Intron 1 of 15	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.-18-3243T>G		intron_variant	Intron 1 of 15	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes AF: 0.544 AC: 82434 AN: 151544 Hom.: 22945 Cov.: 32

Gnomad AFR AF: 0.496

Gnomad AMI AF: 0.510

Gnomad AMR AF: 0.633

Gnomad ASJ AF: 0.525

Gnomad EAS AF: 0.811

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.577

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

GnomAD4 genome AF: 0.544 AC: 82492 AN: 151662 Hom.: 22957 Cov.: 32 AF XY: 0.546 AC XY: 40464 AN XY: 74116

African (AFR) AF: 0.496 AC: 20549 AN: 41404

American (AMR) AF: 0.633 AC: 9661 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.525 AC: 1820 AN: 3468

East Asian (EAS) AF: 0.810 AC: 4198 AN: 5180

South Asian (SAS) AF: 0.642 AC: 3094 AN: 4816

European-Finnish (FIN) AF: 0.468 AC: 4895 AN: 10462

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.538 AC: 36444 AN: 67764

Other (OTH) AF: 0.575 AC: 1212 AN: 2108

Alfa AF: 0.550 Hom.: 50833

Bravo AF: 0.559

Asia WGS AF: 0.714 AC: 2460 AN: 3450

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.4
DANN	Benign	0.62
PhyloP100		-0.60
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: rs11954856; hg19: chr5-112087327;