5-112707795-C-A

Position:

chr5-112707795-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001407446.1(APC):c.78C>A(p.Ser26Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,370,658 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0084 ( 19 hom., cov: 32)

Exomes 𝑓: 0.00082 ( 14 hom. )

Consequence

APC
NM_001407446.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 2.81

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00633198).

BP6

Variant 5-112707795-C-A is Benign according to our data. Variant chr5-112707795-C-A is described in ClinVar as [Benign]. Clinvar id is 133505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00842 (1283/152296) while in subpopulation AFR AF= 0.0296 (1229/41576). AF 95% confidence interval is 0.0282. There are 19 homozygotes in gnomad4. There are 592 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1283 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein
APC	NM_001407446.1 linkuse as main transcript	c.78C>A	p.Ser26Arg	missense_variant	1/16	NP_001394375.1
APC	NM_001354897.2 linkuse as main transcript	c.78C>A	p.Ser26Arg	missense_variant	1/15	NP_001341826.1
APC	NM_001127511.3 linkuse as main transcript	c.78C>A	p.Ser26Arg	missense_variant	1/14	NP_001120983.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	Appris
APC	ENST00000507379.6 linkuse as main transcript	c.78C>A	p.Ser26Arg	missense_variant	1/14	2	ENSP00000423224
APC	ENST00000509732.6 linkuse as main transcript	c.-19+146C>A		intron_variant		4	ENSP00000426541	P1
APC	ENST00000505350.2 linkuse as main transcript	c.78C>A	p.Ser26Arg	missense_variant, NMD_transcript_variant	1/16	3	ENSP00000481752

Frequencies

GnomAD3 genomes

AF:

0.00838

AC:

1275

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0294

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

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:

0.0000441

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00191

AC:

257

AN:

134852

Hom.:

AF XY:

0.00155

AC XY:

114

AN XY:

73416

show subpopulations

Gnomad AFR exome

AF:

0.0312

Gnomad AMR exome

AF:

0.00204

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:

0.0000753

Gnomad OTH exome

AF:

0.000482

GnomAD4 exome

AF:

0.000818

AC:

997

AN:

1218362

Hom.:

Cov.:

AF XY:

0.000707

AC XY:

421

AN XY:

595224

show subpopulations

Gnomad4 AFR exome

AF:

0.0297

Gnomad4 AMR exome

AF:

0.00205

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000910

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000824

Gnomad4 OTH exome

AF:

0.00155

GnomAD4 genome

AF:

0.00842

AC:

1283

AN:

152296

Hom.:

Cov.:

AF XY:

0.00795

AC XY:

592

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0296

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00406

Hom.:

Bravo

AF:

0.00937

ExAC

AF:

0.000922

AC:

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 02, 2017	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2013	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. -

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	Counsyl	Feb 10, 2016	- -

Familial multiple polyposis syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Oct 13, 2015

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 11, 2022

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Vantari Genetics

Feb 04, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

0.11

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0063

MetaSVM

Uncertain

0.14

MutationTaster

Benign

1.0

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.38

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

MutPred

0.22

Loss of glycosylation at S26 (P = 0.0205);

MVP

0.73

ClinPred

0.19

GERP RS

4.0

Splicing

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