5-112707836-G-C

Position:

chr5-112707836-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001407446.1(APC):c.119G>C(p.Ser40Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,370,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

APC
NM_001407446.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7O:1

Conservation

PhyloP100: 0.367

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:

APC (HGNC:):

APC links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08780664).

BP6

Variant 5-112707836-G-C is Benign according to our data. Variant chr5-112707836-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133506.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, not_provided=1, Benign=1}. Variant chr5-112707836-G-C is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein	UniProt
APC	NM_001407446.1 linkuse as main transcript	c.119G>C	p.Ser40Thr	missense_variant	1/16	NP_001394375.1
APC	NM_001354897.2 linkuse as main transcript	c.119G>C	p.Ser40Thr	missense_variant	1/15	NP_001341826.1
APC	NM_001127511.3 linkuse as main transcript	c.119G>C	p.Ser40Thr	missense_variant	1/14	NP_001120983.2	P25054-3Q4LE70

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
APC	ENST00000507379.6 linkuse as main transcript	c.119G>C	p.Ser40Thr	missense_variant	1/14	2	ENSP00000423224.2	A0A2Q2SV78
APC	ENST00000509732.6 linkuse as main transcript	c.-19+187G>C		intron_variant		4	ENSP00000426541.2	D6RFL6
APC	ENST00000505350.2 linkuse as main transcript	n.119G>C		non_coding_transcript_exon_variant	1/16	3	ENSP00000481752.1	A0A087WYF3

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000294

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000141

AC:

AN:

134512

Hom.:

AF XY:

0.000109

AC XY:

AN XY:

73246

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000409

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:

0.000322

Gnomad OTH exome

AF:

0.000242

GnomAD4 exome

AF:

0.000150

AC:

183

AN:

1218210

Hom.:

Cov.:

AF XY:

0.000156

AC XY:

AN XY:

595138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000325

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000763

Gnomad4 NFE exome

AF:

0.000182

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000145

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000132

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 30, 2017	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

APC-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 06, 2024

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

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.53

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.28

MetaRNN

Benign

0.088

MetaSVM

Benign

-0.51

PROVEAN

Benign

-0.52

REVEL

Benign

0.11

Sift

Benign

0.13

Sift4G

Uncertain

0.017

MVP

0.70

ClinPred

0.071

GERP RS

1.2

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