5-112775612-TAAA-TAAAA

Position:

• chr5-112775612-TAAA-TAAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000038.6(APC):​c.423-4dup variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0514 in 1,091,404 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.059 (0 hom.)
• Consequence: APC NM_000038.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.937

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 -16 ACMG points.

• BP6: Variant 5-112775612-T-TA is Benign according to our data. Variant chr5-112775612-T-TA is described in ClinVar as [Likely_benign]. Clinvar id is 802132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0625 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.423-4dup		splice_polypyrimidine_tract_variant, intron_variant		ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.423-4dup		splice_polypyrimidine_tract_variant, intron_variant		5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 217 AN: 143672 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00258

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00736

Gnomad SAS AF: 0.00437

Gnomad FIN AF: 0.00106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000826

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0589 AC: 55865 AN: 947672 Hom.: 0 Cov.: 0 AF XY: 0.0571 AC XY: 27041 AN XY: 473928

Gnomad4 AFR exome AF: 0.0504

Gnomad4 AMR exome AF: 0.0401

Gnomad4 ASJ exome AF: 0.0498

Gnomad4 EAS exome AF: 0.0520

Gnomad4 SAS exome AF: 0.0474

Gnomad4 FIN exome AF: 0.0339

Gnomad4 NFE exome AF: 0.0630

Gnomad4 OTH exome AF: 0.0567

GnomAD4 genome AF: 0.00151 AC: 217 AN: 143732 Hom.: 1 Cov.: 32 AF XY: 0.00166 AC XY: 116 AN XY: 69738

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.00258

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00738

Gnomad4 SAS AF: 0.00438

Gnomad4 FIN AF: 0.00106

Gnomad4 NFE AF: 0.000826

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Gastric cancer;C0346629:Colorectal cancer;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1;C4749917:Gastric adenocarcinoma and proximal polyposis of the stomach Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 10, 2021

- -

Familial adenomatous polyposis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Mar 23, 2020

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs730881230; hg19: chr5-112111309;