5-112737096-A-G

Variant names:

• chr5-112737096-A-G
• rs2464810
• NM_001407446.1:c.165+29214A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001407446.1(APC):​c.165+29214A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.086 in 152,294 control chromosomes in the GnomAD database, including 616 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.086 (616 hom., cov: 32)
• Consequence: APC NM_001407446.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.06
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-112737096-A-G is Benign according to our data. Variant chr5-112737096-A-G is described in ClinVar as Benign. ClinVar VariationId is 386418.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.094 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_001407446.1	c.165+29214A>G		intron_variant	Intron 1 of 15		NP_001394375.1
APC	NM_001407447.1	c.-18-17777A>G		intron_variant	Intron 1 of 16		NP_001394376.1
APC	NM_001407448.1	c.-18-17777A>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.-18-17777A>G		intron_variant	Intron 1 of 15	4		ENSP00000426541.2
APC	ENST00000507379.6	c.165+29214A>G		intron_variant	Intron 1 of 13	2		ENSP00000423224.2
APC	ENST00000505350.2	n.166-17777A>G		intron_variant	Intron 1 of 15	3		ENSP00000481752.1
APC	ENST00000713636.1	n.-18-17777A>G		intron_variant	Intron 1 of 16			ENSP00000518937.1

Frequencies

GnomAD3 genomes AF: 0.0860 AC: 13094 AN: 152178 Hom.: 618 Cov.: 32

Gnomad AFR AF: 0.0965

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.0640

Gnomad ASJ AF: 0.0695

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0911

Gnomad FIN AF: 0.0690

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0937

Gnomad OTH AF: 0.0850

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

GnomAD4 genome AF: 0.0860 AC: 13103 AN: 152294 Hom.: 616 Cov.: 32 AF XY: 0.0852 AC XY: 6341 AN XY: 74468

African (AFR) AF: 0.0965 AC: 4010 AN: 41560

American (AMR) AF: 0.0640 AC: 979 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0695 AC: 241 AN: 3468

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.0909 AC: 439 AN: 4828

European-Finnish (FIN) AF: 0.0690 AC: 733 AN: 10620

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.0937 AC: 6371 AN: 68014

Other (OTH) AF: 0.0836 AC: 177 AN: 2116

Alfa AF: 0.0826 Hom.: 720

Bravo AF: 0.0846

Asia WGS AF: 0.0340 AC: 118 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 25, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.8
DANN	Benign	0.61
PhyloP100		1.1
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: rs2464810; hg19: chr5-112072793;