rs41115

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000038.6(APC):c.4479G>A(p.Thr1493Thr) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T1493T) has been classified as Likely 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

Publications

114 publications found

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 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

APC links:

ENSG00000258864 (HGNC:):

ENSG00000258864 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 42242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
APC	NM_000038.6 link	c.4479G>A	p.Thr1493Thr	synonymous_variant	Exon 16 of 16	ENST00000257430.9	NP_000029.2	P25054-1Q4LE70

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9 link	c.4479G>A	p.Thr1493Thr	synonymous_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4		P25054-1
ENSG00000258864	ENST00000520401.1 link	n.228+11101G>A		intron_variant	Intron 3 of 7	3		ENSP00000454861.1		H3BNH8

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

GnomAD2 exomes

AF:

0.650

AC:

162664

AN:

250358

AF XY:

0.649

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 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

African (AFR)

AF:

0.520

AC:

17411

AN:

33466

American (AMR)

AF:

0.727

AC:

32481

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.582

AC:

15209

AN:

26132

East Asian (EAS)

AF:

0.840

AC:

33361

AN:

39700

South Asian (SAS)

AF:

0.709

AC:

61156

AN:

86250

European-Finnish (FIN)

AF:

0.573

AC:

30594

AN:

53414

Middle Eastern (MID)

AF:

0.614

AC:

3540

AN:

5768

European-Non Finnish (NFE)

AF:

0.616

AC:

685244

AN:

1111914

Other (OTH)

AF:

0.633

AC:

38211

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

21104

42208

63312

84416

105520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18554

37108

55662

74216

92770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.602

AC:

91393

AN:

151928

Hom.:

27967

Cov.:

AF XY:

0.603

AC XY:

44806

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.535

AC:

22134

AN:

41406

American (AMR)

AF:

0.669

AC:

10221

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.567

AC:

1969

AN:

3470

East Asian (EAS)

AF:

0.820

AC:

4247

AN:

5182

South Asian (SAS)

AF:

0.731

AC:

3517

AN:

4814

European-Finnish (FIN)

AF:

0.537

AC:

5646

AN:

10520

Middle Eastern (MID)

AF:

0.633

AC:

186

AN:

294

European-Non Finnish (NFE)

AF:

0.613

AC:

41624

AN:

67946

Other (OTH)

AF:

0.610

AC:

1289

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1833

3667

5500

7334

9167

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

764

1528

2292

3056

3820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.611

Hom.:

45518

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

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

- -

Jul 27, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 16, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:3

Oct 31, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 18, 2016

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 21, 2021

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial adenomatous polyposis 1

Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

May 24, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

APC-Associated Polyposis Disorders

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Systems Biology Platform Zhejiang California International NanoSystems Institute

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

2.6

(source)

DANN

Benign

0.77

PhyloP100

0.092

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over