rs75580617

Positions:

• chr5-112707473-A-C

Variant summary

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

The 5-112707473-A-C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0393 in 417,264 control chromosomes in the GnomAD database, including 681 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (329 hom., cov: 33)
  • Exomes 𝑓: 0.035 (352 hom.)
• Consequence: APC NM_001407446.1 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0670

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=-0.81).
• BP6: Variant 5-112707473-A-C is Benign according to our data. Variant chr5-112707473-A-C is described in ClinVar as [Benign]. Clinvar id is 379248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_001127511.3			upstream_gene_variant			NP_001120983.2
APC	NM_001354895.2			upstream_gene_variant			NP_001341824.1
APC	NM_001354897.2			upstream_gene_variant			NP_001341826.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000507379.6			upstream_gene_variant		2		ENSP00000423224
APC	ENST00000509732.6			upstream_gene_variant		4		ENSP00000426541	P1
APC	ENST00000505350.2			upstream_gene_variant		3		ENSP00000481752

Frequencies

GnomAD3 genomes AF: 0.0472 AC: 7180 AN: 152174 Hom.: 328 Cov.: 33

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0237

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.0697

Gnomad FIN AF: 0.00489

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0592

GnomAD4 exome AF: 0.0348 AC: 9219 AN: 264972 Hom.: 352 Cov.: 2 AF XY: 0.0367 AC XY: 5040 AN XY: 137444

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.0207

Gnomad4 ASJ exome AF: 0.0341

Gnomad4 EAS exome AF: 0.111

Gnomad4 SAS exome AF: 0.0616

Gnomad4 FIN exome AF: 0.00698

Gnomad4 NFE exome AF: 0.0173

Gnomad4 OTH exome AF: 0.0349

GnomAD4 genome AF: 0.0472 AC: 7187 AN: 152292 Hom.: 329 Cov.: 33 AF XY: 0.0476 AC XY: 3542 AN XY: 74472

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0236

Gnomad4 ASJ AF: 0.0311

Gnomad4 EAS AF: 0.134

Gnomad4 SAS AF: 0.0695

Gnomad4 FIN AF: 0.00489

Gnomad4 NFE AF: 0.0173

Gnomad4 OTH AF: 0.0586

Alfa AF: 0.0320 Hom.: 20

Bravo AF: 0.0519

Asia WGS AF: 0.112 AC: 388 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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	GeneDx	Nov 16, 2016	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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 22, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.0
DANN	Benign	0.71

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs75580617; hg19: chr5-112043170; COSMIC: COSV71820291;