5-112716131-G-C

Variant names:

• chr5-112716131-G-C
• rs1661035
• NM_001407446.1:c.165+8249G>C

Variant summary

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

The NM_001407446.1(APC):​c.165+8249G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.66 in 151,870 control chromosomes in the GnomAD database, including 33,390 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.66 (33390 hom., cov: 31)
• Consequence: APC NM_001407446.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.33
• Publications: 4 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=-1.04).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.784 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_001407446.1	c.165+8249G>C		intron_variant	Intron 1 of 15		NP_001394375.1
APC	NM_001407447.1	c.-19+8249G>C		intron_variant	Intron 1 of 16		NP_001394376.1
APC	NM_001407448.1	c.-19+8482G>C		intron_variant	Intron 1 of 16		NP_001394377.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000509732.6	c.-19+8482G>C		intron_variant	Intron 1 of 15	4		ENSP00000426541.2
APC	ENST00000507379.6	c.165+8249G>C		intron_variant	Intron 1 of 13	2		ENSP00000423224.2
APC	ENST00000505350.2	n.165+8249G>C		intron_variant	Intron 1 of 15	3		ENSP00000481752.1
APC	ENST00000713636.1	n.-19+8249G>C		intron_variant	Intron 1 of 16			ENSP00000518937.1

Frequencies

GnomAD3 genomes AF: 0.660 AC: 100130 AN: 151752 Hom.: 33360 Cov.: 31

Gnomad AFR AF: 0.702

Gnomad AMI AF: 0.633

Gnomad AMR AF: 0.704

Gnomad ASJ AF: 0.593

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.733

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.662

Gnomad NFE AF: 0.630

Gnomad OTH AF: 0.669

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

GnomAD4 genome AF: 0.660 AC: 100217 AN: 151870 Hom.: 33390 Cov.: 31 AF XY: 0.660 AC XY: 48950 AN XY: 74204

African (AFR) AF: 0.702 AC: 29092 AN: 41446

American (AMR) AF: 0.704 AC: 10759 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.593 AC: 2057 AN: 3470

East Asian (EAS) AF: 0.805 AC: 4157 AN: 5166

South Asian (SAS) AF: 0.733 AC: 3523 AN: 4808

European-Finnish (FIN) AF: 0.539 AC: 5645 AN: 10470

Middle Eastern (MID) AF: 0.671 AC: 196 AN: 292

European-Non Finnish (NFE) AF: 0.630 AC: 42807 AN: 67916

Other (OTH) AF: 0.666 AC: 1406 AN: 2112

Alfa AF: 0.502 Hom.: 1273

Bravo AF: 0.677

Asia WGS AF: 0.756 AC: 2621 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.40
DANN	Benign	0.43
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1661035; hg19: chr5-112051828;