rs397768

Variant names:

• chr5-112845879-G-A
• rs397768
• NM_000038.6:c.*1753G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-112845879-G-A
• chr5-112845879-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000038.6(APC):​c.*1753G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.641 in 231,790 control chromosomes in the GnomAD database, including 48,105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.63 (30503 hom., cov: 31)
  • Exomes 𝑓: 0.66 (17602 hom.)
• Consequence: APC NM_000038.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 0.210
• Publications: 26 publications found

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 Gene-Disease associations (from GenCC):

• classic or attenuated familial adenomatous polyposis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• desmoid tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• familial adenomatous polyposis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• APC-related attenuated familial adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Turcot syndrome with polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000258864 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-112845879-G-A is Benign according to our data. Variant chr5-112845879-G-A is described in ClinVar as Benign. ClinVar VariationId is 83263.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.*1753G>A		3_prime_UTR_variant	Exon 16 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.*1753G>A		3_prime_UTR_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.229-10770G>A		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes AF: 0.631 AC: 95738 AN: 151804 Hom.: 30487 Cov.: 31

Gnomad AFR AF: 0.604

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.692

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.821

Gnomad SAS AF: 0.736

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.627

Gnomad OTH AF: 0.640

GnomAD4 exome AF: 0.660 AC: 52686 AN: 79868 Hom.: 17602 Cov.: 0 AF XY: 0.658 AC XY: 24159 AN XY: 36720

African (AFR) AF: 0.607 AC: 2324 AN: 3826

American (AMR) AF: 0.712 AC: 1763 AN: 2476

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 3055 AN: 5044

East Asian (EAS) AF: 0.848 AC: 9515 AN: 11218

South Asian (SAS) AF: 0.732 AC: 501 AN: 684

European-Finnish (FIN) AF: 0.518 AC: 29 AN: 56

Middle Eastern (MID) AF: 0.611 AC: 297 AN: 486

European-Non Finnish (NFE) AF: 0.625 AC: 30890 AN: 49390

Other (OTH) AF: 0.645 AC: 4312 AN: 6688

GnomAD4 genome AF: 0.631 AC: 95809 AN: 151922 Hom.: 30503 Cov.: 31 AF XY: 0.632 AC XY: 46922 AN XY: 74234

African (AFR) AF: 0.604 AC: 25036 AN: 41442

American (AMR) AF: 0.692 AC: 10566 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 2044 AN: 3468

East Asian (EAS) AF: 0.820 AC: 4233 AN: 5160

South Asian (SAS) AF: 0.736 AC: 3542 AN: 4812

European-Finnish (FIN) AF: 0.539 AC: 5678 AN: 10526

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.627 AC: 42595 AN: 67930

Other (OTH) AF: 0.637 AC: 1345 AN: 2112

Alfa AF: 0.615 Hom.: 4241

Bravo AF: 0.643

Asia WGS AF: 0.760 AC: 2635 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

APC-Associated Polyposis Disorders Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Systems Biology Platform Zhejiang California International NanoSystems Institute

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.4
DANN	Benign	0.51
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs397768; hg19: chr5-112181576; COSMIC: COSV57321672;