rs42427

Positions:

Variant summary

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

The NM_000038.6(APC):c.5034G>A(p.Gly1678=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 1,613,474 control chromosomes in the GnomAD database, including 322,713 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.60 ( 28272 hom., cov: 32)

Exomes 𝑓: 0.63 ( 294441 hom. )

Consequence

APC
NM_000038.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17O:1

Conservation

PhyloP100: 0.493

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 5-112840628-G-A is Benign according to our data. Variant chr5-112840628-G-A is described in ClinVar as [Benign]. Clinvar id is 42243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112840628-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.493 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.5034G>A	p.Gly1678=	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.5034G>A	p.Gly1678=	synonymous_variant	16/16	5	NM_000038.6	ENSP00000257430	P1	P25054-1

Frequencies

GnomAD3 genomes

AF:

0.605

AC:

91862

AN:

151912

Hom.:

28255

Cov.:

show subpopulations

Gnomad AFR

AF:

0.536

Gnomad AMI

AF:

0.614

Gnomad AMR

AF:

0.674

Gnomad ASJ

AF:

0.567

Gnomad EAS

AF:

0.820

Gnomad SAS

AF:

0.730

Gnomad FIN

AF:

0.537

Gnomad MID

AF:

0.623

Gnomad NFE

AF:

0.618

Gnomad OTH

AF:

0.614

GnomAD3 exomes

AF:

0.652

AC:

163051

AN:

249920

Hom.:

54165

AF XY:

0.652

AC XY:

88074

AN XY:

135128

show subpopulations

Gnomad AFR exome

AF:

0.535

Gnomad AMR exome

AF:

0.736

Gnomad ASJ exome

AF:

0.582

Gnomad EAS exome

AF:

0.822

Gnomad SAS exome

AF:

0.713

Gnomad FIN exome

AF:

0.560

Gnomad NFE exome

AF:

0.623

Gnomad OTH exome

AF:

0.655

GnomAD4 exome

AF:

0.632

AC:

923861

AN:

1461444

Hom.:

294441

Cov.:

AF XY:

0.634

AC XY:

460903

AN XY:

727040

show subpopulations

Gnomad4 AFR exome

AF:

0.522

Gnomad4 AMR exome

AF:

0.729

Gnomad4 ASJ exome

AF:

0.582

Gnomad4 EAS exome

AF:

0.840

Gnomad4 SAS exome

AF:

0.709

Gnomad4 FIN exome

AF:

0.574

Gnomad4 NFE exome

AF:

0.622

Gnomad4 OTH exome

AF:

0.636

GnomAD4 genome

AF:

0.605

AC:

91931

AN:

152030

Hom.:

28272

Cov.:

AF XY:

0.606

AC XY:

45044

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.536

Gnomad4 AMR

AF:

0.674

Gnomad4 ASJ

AF:

0.567

Gnomad4 EAS

AF:

0.820

Gnomad4 SAS

AF:

0.730

Gnomad4 FIN

AF:

0.537

Gnomad4 NFE

AF:

0.618

Gnomad4 OTH

AF:

0.612

Alfa

AF:

0.617

Hom.:

37193

Bravo

AF:

0.613

Asia WGS

AF:

0.754

AC:

2616

AN:

3476

EpiCase

AF:

0.613

EpiControl

AF:

0.618

ClinVar

Significance: Benign

Submissions summary: Benign:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -
Benign, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 01, 2008	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 18, 2016	- -
Benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Dec 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 21, 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. -

Familial adenomatous polyposis 1

Benign:2

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

not provided

Benign:2

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

Carcinoma of colon

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The c.5034G>A, p.Gly1678Gly silent variant, located in exon 14 of APC, is not expected to have clinical significance because it does not alter an amino acid residue, is not located near a splice junction, is listed in dbSNP (rs_id: rs42427) as a common polymorphism. Based on the above information, this is a benign variant. -

APC-Associated Polyposis Disorders

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

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

-0.82

CADD

Benign

3.0

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