5-112707375-A-G

Variant names:

• chr5-112707375-A-G
• rs13180781
• NM_001407446.1:c.-343A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001407446.1(APC):​c.-343A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0704 in 339,774 control chromosomes in the GnomAD database, including 1,122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (490 hom., cov: 33)
  • Exomes 𝑓: 0.072 (632 hom.)
• Consequence: APC NM_001407446.1 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.48

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 5-112707375-A-G is Benign according to our data. Variant chr5-112707375-A-G is described in ClinVar as [Benign]. Clinvar id is 386417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_001407446.1	c.-343A>G		upstream_gene_variant			NP_001394375.1
APC	NM_001407447.1	c.-526A>G		upstream_gene_variant			NP_001394376.1
APC	NM_001407448.1	c.-293A>G		upstream_gene_variant			NP_001394377.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000509732.6	c.-293A>G		upstream_gene_variant		4		ENSP00000426541.2
APC	ENST00000507379.6	c.-343A>G		upstream_gene_variant		2		ENSP00000423224.2
APC	ENST00000505350.2	n.-343A>G		upstream_gene_variant		3		ENSP00000481752.1

Frequencies

GnomAD3 genomes AF: 0.0679 AC: 10333 AN: 152282 Hom.: 487 Cov.: 33

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.0632

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0972

Gnomad OTH AF: 0.0735

GnomAD4 exome AF: 0.0724 AC: 13568 AN: 187374 Hom.: 632 AF XY: 0.0690 AC XY: 6585 AN XY: 95392

Gnomad4 AFR exome AF: 0.0181

Gnomad4 AMR exome AF: 0.0533

Gnomad4 ASJ exome AF: 0.102

Gnomad4 EAS exome AF: 0.000200

Gnomad4 SAS exome AF: 0.0264

Gnomad4 FIN exome AF: 0.0843

Gnomad4 NFE exome AF: 0.0938

Gnomad4 OTH exome AF: 0.0796

GnomAD4 genome AF: 0.0679 AC: 10346 AN: 152400 Hom.: 490 Cov.: 33 AF XY: 0.0667 AC XY: 4968 AN XY: 74530

Gnomad4 AFR AF: 0.0178

Gnomad4 AMR AF: 0.0631

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0215

Gnomad4 FIN AF: 0.115

Gnomad4 NFE AF: 0.0972

Gnomad4 OTH AF: 0.0784

Alfa AF: 0.0775 Hom.: 75

Bravo AF: 0.0634

Asia WGS AF: 0.0420 AC: 145 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Nov 16, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

APC-related disorder Benign:1

May 04, 2023

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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_noAF	Benign	-0.77
CADD	Benign	0.24
DANN	Benign	0.70

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs13180781; hg19: chr5-112043072;