rs41116

Positions:

• chr5-112845224-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000038.6(APC):​c.*1098T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 232,296 control chromosomes in the GnomAD database, including 26,028 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.40 (14803 hom., cov: 32)
  • Exomes 𝑓: 0.51 (11225 hom.)
• Consequence: APC NM_000038.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 1.33

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 5-112845224-T-C is Benign according to our data. Variant chr5-112845224-T-C is described in ClinVar as [Benign]. Clinvar id is 83260.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.*1098T>C		3_prime_UTR_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.*1098T>C		3_prime_UTR_variant	16/16	5	NM_000038.6	P1
APC	ENST00000508376.6	c.*1098T>C		3_prime_UTR_variant	17/17	1		P1
APC	ENST00000509732.6	c.*1098T>C		3_prime_UTR_variant	16/16	4		P1
APC	ENST00000505350.2	c.*9636T>C		3_prime_UTR_variant, NMD_transcript_variant	16/16	3

Frequencies

GnomAD3 genomes AF: 0.402 AC: 61122 AN: 151964 Hom.: 14805 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.566

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.440

GnomAD4 exome AF: 0.513 AC: 41126 AN: 80214 Hom.: 11225 Cov.: 0 AF XY: 0.513 AC XY: 18959 AN XY: 36942

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.587

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.739

Gnomad4 SAS exome AF: 0.545

Gnomad4 FIN exome AF: 0.442

Gnomad4 NFE exome AF: 0.495

Gnomad4 OTH exome AF: 0.473

GnomAD4 genome AF: 0.402 AC: 61123 AN: 152082 Hom.: 14803 Cov.: 32 AF XY: 0.405 AC XY: 30138 AN XY: 74334

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.566

Gnomad4 ASJ AF: 0.482

Gnomad4 EAS AF: 0.670

Gnomad4 SAS AF: 0.555

Gnomad4 FIN AF: 0.412

Gnomad4 NFE AF: 0.494

Gnomad4 OTH AF: 0.438

Alfa AF: 0.450 Hom.: 4636

Bravo AF: 0.405

Asia WGS AF: 0.568 AC: 1970 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

APC-Associated Polyposis Disorders Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial colorectal cancer Other:1

other, no assertion criteria provided

literature only

Systems Biology Platform Zhejiang California International NanoSystems Institute

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.8
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs41116; hg19: chr5-112180921; COSMIC: COSV57321664; COSMIC: COSV57321664;