5-112707586-G-T

Position:

• chr5-112707586-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001407446.1(APC):​c.-132G>T 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 0.00106 in 970,022 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00099 (5 hom.)
• Consequence: APC NM_001407446.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.113

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=-0.64).
• BP6: Variant 5-112707586-G-T is Benign according to our data. Variant chr5-112707586-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 469835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112707586-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00142 (213/149642) while in subpopulation EAS AF= 0.0297 (154/5178). AF 95% confidence interval is 0.0259. There are 2 homozygotes in gnomad4. There are 112 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 213 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_001407446.1	c.-132G>T		5_prime_UTR_premature_start_codon_gain_variant	1/16		NP_001394375.1
APC	NM_001407447.1	c.-315G>T		5_prime_UTR_premature_start_codon_gain_variant	1/17		NP_001394376.1
APC	NM_001407448.1	c.-82G>T		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.-82G>T		5_prime_UTR_premature_start_codon_gain_variant	1/16	4		ENSP00000426541.2
APC	ENST00000507379	c.-132G>T		5_prime_UTR_premature_start_codon_gain_variant	1/14	2		ENSP00000423224.2
APC	ENST00000509732	c.-82G>T		5_prime_UTR_variant	1/16	4		ENSP00000426541.2

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 213 AN: 149522 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000655

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000333

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0295

Gnomad SAS AF: 0.00107

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000272

Gnomad OTH AF: 0.00243

GnomAD4 exome AF: 0.000989 AC: 811 AN: 820380 Hom.: 5 Cov.: 11 AF XY: 0.000990 AC XY: 401 AN XY: 405170

Gnomad4 AFR exome AF: 0.000300

Gnomad4 AMR exome AF: 0.000170

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0228

Gnomad4 SAS exome AF: 0.00100

Gnomad4 FIN exome AF: 0.0000910

Gnomad4 NFE exome AF: 0.000278

Gnomad4 OTH exome AF: 0.00218

GnomAD4 genome AF: 0.00142 AC: 213 AN: 149642 Hom.: 2 Cov.: 33 AF XY: 0.00153 AC XY: 112 AN XY: 73246

Gnomad4 AFR AF: 0.000653

Gnomad4 AMR AF: 0.000332

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0297

Gnomad4 SAS AF: 0.000854

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000272

Gnomad4 OTH AF: 0.00241

Alfa AF: 0.0000531 Hom.: 0

Bravo AF: 0.00186

Asia WGS AF: 0.0120 AC: 43 AN: 3470

ClinVar

Significance: Benign/Likely 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	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2017	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

Jan 27, 2024

- -

APC-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 15, 2020

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	-0.64
CADD	Benign	7.3
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: rs182500056; hg19: chr5-112043283;