rs454886

Variant names:

• chr5-112810420-A-G
• rs454886
• NM_000038.6:c.835-5075A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-112810420-A-G
• chr5-112810420-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000038.6(APC):​c.835-5075A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 207,972 control chromosomes in the GnomAD database, including 10,892 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars).

• Frequency:
  • Genomes: 𝑓 0.27 (7235 hom., cov: 32)
  • Exomes 𝑓: 0.35 (3657 hom.)
• Consequence: APC NM_000038.6 intron
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: -0.354
• Publications: 29 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.835-5075A>G		intron_variant	Intron 8 of 15	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.835-5075A>G		intron_variant	Intron 8 of 15	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41458 AN: 152068 Hom.: 7235 Cov.: 32

Gnomad AFR AF: 0.0800

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.450

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.623

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.297

GnomAD4 exome AF: 0.346 AC: 19282 AN: 55786 Hom.: 3657 AF XY: 0.353 AC XY: 10449 AN XY: 29560

African (AFR) AF: 0.0771 AC: 81 AN: 1050

American (AMR) AF: 0.524 AC: 1331 AN: 2538

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 390 AN: 1294

East Asian (EAS) AF: 0.640 AC: 1356 AN: 2118

South Asian (SAS) AF: 0.414 AC: 3906 AN: 9446

European-Finnish (FIN) AF: 0.267 AC: 732 AN: 2740

Middle Eastern (MID) AF: 0.325 AC: 74 AN: 228

European-Non Finnish (NFE) AF: 0.312 AC: 10432 AN: 33424

Other (OTH) AF: 0.332 AC: 980 AN: 2948

GnomAD4 genome AF: 0.272 AC: 41463 AN: 152186 Hom.: 7235 Cov.: 32 AF XY: 0.277 AC XY: 20588 AN XY: 74402

African (AFR) AF: 0.0798 AC: 3316 AN: 41564

American (AMR) AF: 0.450 AC: 6879 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 997 AN: 3468

East Asian (EAS) AF: 0.622 AC: 3220 AN: 5176

South Asian (SAS) AF: 0.434 AC: 2096 AN: 4826

European-Finnish (FIN) AF: 0.239 AC: 2536 AN: 10592

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.314 AC: 21351 AN: 67978

Other (OTH) AF: 0.297 AC: 626 AN: 2108

Alfa AF: 0.314 Hom.: 13753

Bravo AF: 0.285

Asia WGS AF: 0.470 AC: 1632 AN: 3476

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial colorectal cancer Other:1

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Systems Biology Platform Zhejiang California International NanoSystems Institute

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.0
DANN	Benign	0.61
PhyloP100		-0.35
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: rs454886; hg19: chr5-112146117;