5-112723897-A-G

Variant names:

• chr5-112723897-A-G
• rs3846716
• NM_001407446.1:c.165+16015A>G

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+16015A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 151,848 control chromosomes in the GnomAD database, including 21,436 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 0.52 (21436 hom., cov: 31)
• Consequence: APC NM_001407446.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.202
• Publications: 9 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=-0.99).
• 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+16015A>G		intron_variant	Intron 1 of 15		NP_001394375.1
APC	NM_001407447.1	c.-19+16015A>G		intron_variant	Intron 1 of 16		NP_001394376.1
APC	NM_001407448.1	c.-19+16248A>G		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+16248A>G		intron_variant	Intron 1 of 15	4		ENSP00000426541.2
APC	ENST00000507379.6	c.165+16015A>G		intron_variant	Intron 1 of 13	2		ENSP00000423224.2
APC	ENST00000505350.2	n.165+16015A>G		intron_variant	Intron 1 of 15	3		ENSP00000481752.1
APC	ENST00000713636.1	n.-19+16015A>G		intron_variant	Intron 1 of 16			ENSP00000518937.1

Frequencies

GnomAD3 genomes AF: 0.524 AC: 79557 AN: 151730 Hom.: 21426 Cov.: 31

Gnomad AFR AF: 0.466

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.618

Gnomad ASJ AF: 0.514

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.637

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.559

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

GnomAD4 genome AF: 0.524 AC: 79615 AN: 151848 Hom.: 21436 Cov.: 31 AF XY: 0.527 AC XY: 39112 AN XY: 74230

African (AFR) AF: 0.467 AC: 19303 AN: 41366

American (AMR) AF: 0.618 AC: 9437 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 1784 AN: 3472

East Asian (EAS) AF: 0.805 AC: 4148 AN: 5154

South Asian (SAS) AF: 0.637 AC: 3067 AN: 4818

European-Finnish (FIN) AF: 0.458 AC: 4814 AN: 10516

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.519 AC: 35291 AN: 67948

Other (OTH) AF: 0.557 AC: 1172 AN: 2106

Alfa AF: 0.524 Hom.: 17573

Bravo AF: 0.538

Asia WGS AF: 0.710 AC: 2467 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.92
DANN	Benign	0.76
PhyloP100		0.20
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: rs3846716; hg19: chr5-112059594;