5-112820096-G-C

Variant names:

• chr5-112820096-G-C
• rs501250
• NM_000038.6:c.1312+752G>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.1312+752G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.606 in 151,650 control chromosomes in the GnomAD database, including 28,470 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars).

• Frequency: Genomes: 𝑓 0.61 (28470 hom., cov: 29)
• Consequence: APC NM_000038.6 intron
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 1.20
• Publications: 7 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.882 is higher than 0.05.

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.1312+752G>C		intron	N/A	NP_000029.2
	APC	NM_001407446.1		c.1342+752G>C		intron	N/A	NP_001394375.1
	APC	NM_001354896.2		c.1312+752G>C		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.1312+752G>C		intron	N/A	ENSP00000257430.4
	APC	ENST00000508376.6	TSL:1	c.1312+752G>C		intron	N/A	ENSP00000427089.2
	APC	ENST00000502371.3	TSL:1	n.1312+752G>C		intron	N/A	ENSP00000484935.2

Frequencies

GnomAD3 genomes AF: 0.606 AC: 91873 AN: 151532 Hom.: 28453 Cov.: 29

Gnomad AFR AF: 0.535

Gnomad AMI AF: 0.616

Gnomad AMR AF: 0.671

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.904

Gnomad SAS AF: 0.735

Gnomad FIN AF: 0.537

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.615

Gnomad OTH AF: 0.619

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

GnomAD4 genome AF: 0.606 AC: 91941 AN: 151650 Hom.: 28470 Cov.: 29 AF XY: 0.608 AC XY: 45037 AN XY: 74090

African (AFR) AF: 0.536 AC: 22117 AN: 41280

American (AMR) AF: 0.671 AC: 10203 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 1975 AN: 3468

East Asian (EAS) AF: 0.904 AC: 4656 AN: 5150

South Asian (SAS) AF: 0.734 AC: 3542 AN: 4824

European-Finnish (FIN) AF: 0.537 AC: 5630 AN: 10488

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.615 AC: 41777 AN: 67926

Other (OTH) AF: 0.615 AC: 1295 AN: 2106

Alfa AF: 0.465 Hom.: 1222

Bravo AF: 0.615

Asia WGS AF: 0.775 AC: 2692 AN: 3476

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	9.3
DANN	Benign	0.53
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs501250; hg19: chr5-112155793;