rs4705559

Variant names:

• chr5-112714425-A-G
• rs4705559
• NM_001407446.1:c.165+6543A>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+6543A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 152,154 control chromosomes in the GnomAD database, including 14,908 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 0.41 (14908 hom., cov: 33)
• Consequence: APC NM_001407446.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.287
• Publications: 5 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=-0.7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_001407446.1	c.165+6543A>G		intron_variant	Intron 1 of 15		NP_001394375.1
APC	NM_001407447.1	c.-19+6543A>G		intron_variant	Intron 1 of 16		NP_001394376.1
APC	NM_001407448.1	c.-19+6776A>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+6776A>G		intron_variant	Intron 1 of 15	4		ENSP00000426541.2
APC	ENST00000507379.6	c.165+6543A>G		intron_variant	Intron 1 of 13	2		ENSP00000423224.2
APC	ENST00000505350.2	n.165+6543A>G		intron_variant	Intron 1 of 15	3		ENSP00000481752.1
APC	ENST00000713636.1	n.-19+6543A>G		intron_variant	Intron 1 of 16			ENSP00000518937.1

Frequencies

GnomAD3 genomes AF: 0.405 AC: 61648 AN: 152036 Hom.: 14909 Cov.: 33

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.568

Gnomad ASJ AF: 0.481

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.442

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

GnomAD4 genome AF: 0.405 AC: 61651 AN: 152154 Hom.: 14908 Cov.: 33 AF XY: 0.408 AC XY: 30386 AN XY: 74388

African (AFR) AF: 0.137 AC: 5699 AN: 41544

American (AMR) AF: 0.568 AC: 8698 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.481 AC: 1668 AN: 3470

East Asian (EAS) AF: 0.671 AC: 3468 AN: 5172

South Asian (SAS) AF: 0.559 AC: 2694 AN: 4820

European-Finnish (FIN) AF: 0.412 AC: 4363 AN: 10578

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.494 AC: 33538 AN: 67956

Other (OTH) AF: 0.440 AC: 929 AN: 2110

Alfa AF: 0.446 Hom.: 2828

Bravo AF: 0.408

Asia WGS AF: 0.576 AC: 2001 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.0
DANN	Benign	0.84
PhyloP100		-0.29
Mutation Taster		=99/1	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs4705559; hg19: chr5-112050122;