5-112707585-C-G

Position:

• chr5-112707585-C-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.-133C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 965,948 control chromosomes in the GnomAD database, including 9,920 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2037 hom., cov: 33)
  • Exomes 𝑓: 0.13 (7883 hom.)
• Consequence: APC NM_001407446.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.62

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 5-112707585-C-G is Benign according to our data. Variant chr5-112707585-C-G is described in ClinVar as [Benign]. Clinvar id is 379246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112707585-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_001407446.1	c.-133C>G		5_prime_UTR_premature_start_codon_gain_variant	1/16		NP_001394375.1
APC	NM_001407447.1	c.-316C>G		5_prime_UTR_premature_start_codon_gain_variant	1/17		NP_001394376.1
APC	NM_001407448.1	c.-83C>G		5_prime_UTR_premature_start_codon_gain_variant	1/17		NP_001394377.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000509732	c.-83C>G		5_prime_UTR_premature_start_codon_gain_variant	1/16	4		ENSP00000426541.2
APC	ENST00000507379	c.-133C>G		5_prime_UTR_premature_start_codon_gain_variant	1/14	2		ENSP00000423224.2
APC	ENST00000509732	c.-83C>G		5_prime_UTR_variant	1/16	4		ENSP00000426541.2

Frequencies

GnomAD3 genomes AF: 0.158 AC: 23982 AN: 152128 Hom.: 2029 Cov.: 33

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.161

GnomAD4 exome AF: 0.134 AC: 108877 AN: 813702 Hom.: 7883 Cov.: 11 AF XY: 0.136 AC XY: 54542 AN XY: 401614

Gnomad4 AFR exome AF: 0.228

Gnomad4 AMR exome AF: 0.0797

Gnomad4 ASJ exome AF: 0.117

Gnomad4 EAS exome AF: 0.114

Gnomad4 SAS exome AF: 0.176

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.129

Gnomad4 OTH exome AF: 0.141

GnomAD4 genome AF: 0.158 AC: 24020 AN: 152246 Hom.: 2037 Cov.: 33 AF XY: 0.157 AC XY: 11682 AN XY: 74456

Gnomad4 AFR AF: 0.225

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.174

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.159

Alfa AF: 0.0489 Hom.: 53

Bravo AF: 0.159

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.9
DANN	Benign	0.85

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs79896135; hg19: chr5-112043282;