rs41115

Positions:

chr5-112840073-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000038.6(APC):c.4479G>A(p.Thr1493=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 1,613,660 control chromosomes in the GnomAD database, including 318,158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.60 ( 27967 hom., cov: 31)

Exomes 𝑓: 0.63 ( 290191 hom. )

Consequence

APC
NM_000038.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18O:1

Conservation

PhyloP100: 0.0920

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 5-112840073-G-A is Benign according to our data. Variant chr5-112840073-G-A is described in ClinVar as [Benign]. Clinvar id is 42242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112840073-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.092 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.4479G>A	p.Thr1493=	synonymous_variant	16/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9 linkuse as main transcript	c.4479G>A	p.Thr1493=	synonymous_variant	16/16	5	NM_000038.6	ENSP00000257430	P1	P25054-1

Frequencies

GnomAD3 genomes

AF:

0.602

AC:

91324

AN:

151810

Hom.:

27950

Cov.:

show subpopulations

Gnomad AFR

AF:

0.534

Gnomad AMI

AF:

0.617

Gnomad AMR

AF:

0.669

Gnomad ASJ

AF:

0.567

Gnomad EAS

AF:

0.820

Gnomad SAS

AF:

0.731

Gnomad FIN

AF:

0.537

Gnomad MID

AF:

0.623

Gnomad NFE

AF:

0.613

Gnomad OTH

AF:

0.612

GnomAD3 exomes

AF:

0.650

AC:

162664

AN:

250358

Hom.:

53850

AF XY:

0.649

AC XY:

87950

AN XY:

135508

show subpopulations

Gnomad AFR exome

AF:

0.533

Gnomad AMR exome

AF:

0.734

Gnomad ASJ exome

AF:

0.582

Gnomad EAS exome

AF:

0.822

Gnomad SAS exome

AF:

0.713

Gnomad FIN exome

AF:

0.559

Gnomad NFE exome

AF:

0.619

Gnomad OTH exome

AF:

0.651

GnomAD4 exome

AF:

0.627

AC:

917207

AN:

1461732

Hom.:

290191

Cov.:

AF XY:

0.629

AC XY:

457710

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.520

Gnomad4 AMR exome

AF:

0.727

Gnomad4 ASJ exome

AF:

0.582

Gnomad4 EAS exome

AF:

0.840

Gnomad4 SAS exome

AF:

0.709

Gnomad4 FIN exome

AF:

0.573

Gnomad4 NFE exome

AF:

0.616

Gnomad4 OTH exome

AF:

0.633

GnomAD4 genome

AF:

0.602

AC:

91393

AN:

151928

Hom.:

27967

Cov.:

AF XY:

0.603

AC XY:

44806

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.535

Gnomad4 AMR

AF:

0.669

Gnomad4 ASJ

AF:

0.567

Gnomad4 EAS

AF:

0.820

Gnomad4 SAS

AF:

0.731

Gnomad4 FIN

AF:

0.537

Gnomad4 NFE

AF:

0.613

Gnomad4 OTH

AF:

0.610

Alfa

AF:

0.613

Hom.:

36825

Bravo

AF:

0.610

Asia WGS

AF:

0.753

AC:

2615

AN:

3476

EpiCase

AF:

0.610

EpiControl

AF:

0.612

ClinVar

Significance: Benign

Submissions summary: Benign:18Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 27, 2020	The p.Thr1493Thr variant in APC is classified as benign because it has been identified in 82% (16364/19946) of East Asian chromosomes, including 6724 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 31, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Dec 21, 2021	- -

Familial adenomatous polyposis 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Gastric cancer;C0346629:Colorectal cancer;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1;C4749917:Gastric adenocarcinoma and proximal polyposis of the stomach

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 24, 2022

- -

APC-Associated Polyposis Disorders

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Carcinoma of colon

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The c.4479G>A, p.Thr1493Thr variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located near a splice junction, and is listed in dbSNP (rs_id: rs41115) as a common polymorphism with a global minor allele frequency of 0.338. It has not been previously identified by our laboratory, but has been reported in the literature in 72/2142 (frequency of 0.033) proband chromosomes from individuals with familiar adenamatous polyposis, colorectal carcinoma, papillary thyroid carcinoma and sporadic ependymoma. It has also been identified in 54/2322 (frequency of 0.023) control chromosomes, increasing the likelihood that the variant has no clinical significance (Rocco_2006, Azzopardi_2008_18199528, Chao_2006_16569251, Curia_2012_21995949, Jasperson_2010_20420945, Kamory_2008_18369740, Onilude_2006_16843107, Schwab_2008_18026870, Subramaniam_2007_18024325, Teijeiro_2009_19095577). In summary, based on the above information, this variant is classified as benign. -

Familial colorectal cancer

Other:1

other, no assertion criteria provided

literature only

Systems Biology Platform Zhejiang California International NanoSystems Institute

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

2.6

DANN

Benign

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over