rs148223181

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000038.6(APC):c.3739G>A(p.Ala1247Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000707 in 1,613,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1247G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.100

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009614021).

BP6

Variant 5-112839333-G-A is Benign according to our data. Variant chr5-112839333-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 184543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112839333-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6 linkuse as main transcript	c.3739G>A	p.Ala1247Thr	missense_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9 linkuse as main transcript	c.3739G>A	p.Ala1247Thr	missense_variant	16/16	5	NM_000038.6	P1	P25054-1

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000962

AC:

AN:

249496

Hom.:

AF XY:

0.0000815

AC XY:

AN XY:

134988

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.0000582

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1460874

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726672

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000473

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00164

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.000472

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 14, 2015	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, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 23, 2016	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 23, 2021	- -

Familial adenomatous polyposis 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 22, 2024	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 12, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	This variant is associated with the following publications: (PMID: 18199528, 24599579, 28576136, 28135145) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 08, 2019

Variant summary: APC c.3739G>A (p.Ala1247Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 282824 control chromosomes, predominantly at a frequency of 0.0016 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 22 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.3739G>A has been reported in the literature in individuals affected with Familial Adenomatous Polyposis and colorectal cancer (Azzopard_2008, Grandval_2014, Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. In addition, Grandval_2014 reports co-occurrence with another pathogenic APC variant (c.3201dup, p.Ser1068Ilefs*13), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

APC-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.37

Cadd

Benign

0.43

Dann

Benign

0.49

DEOGEN2

Benign

0.41

T;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.082

M_CAP

Benign

0.020

MetaRNN

Benign

0.0096

T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

-0.32

N;N;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.72

N;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.88

T;T;T

Sift4G

Benign

0.67

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.041

MVP

0.66

ClinPred

0.0040

GERP RS

-6.1

Varity_R

0.051

gMVP

0.32

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