rs448475

Variant names:

• chr5-112845682-C-G
• rs448475
• NM_000038.6:c.*1556C>G

Your query was ambiguous. Multiple possible variants found:

• chr5-112845682-C-G
• chr5-112845682-C-A
• chr5-112845682-C-T

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.*1556C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 231,660 control chromosomes in the GnomAD database, including 26,071 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.41 (14892 hom., cov: 32)
  • Exomes 𝑓: 0.51 (11179 hom.)
• Consequence: APC NM_000038.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 0.379
• Publications: 20 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: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• 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=-0.87).
• BP6: Variant 5-112845682-C-G is Benign according to our data. Variant chr5-112845682-C-G is described in ClinVar as Benign. ClinVar VariationId is 83262.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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000038.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	NM_000038.6	MANE Select	c.*1556C>G		3_prime_UTR	Exon 16 of 16	NP_000029.2
	APC	NM_001407446.1		c.*1556C>G		3_prime_UTR	Exon 16 of 16	NP_001394375.1
	APC	NM_001354896.2		c.*1556C>G		3_prime_UTR	Exon 17 of 17	NP_001341825.1	R4GMU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000257430.9	TSL:5 MANE Select	c.*1556C>G		3_prime_UTR	Exon 16 of 16	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.*1556C>G		3_prime_UTR	Exon 17 of 17	ENSP00000427089.2	P25054-1
	ENSG00000258864	ENST00000520401.1	TSL:3	n.229-10967C>G		intron	N/A	ENSP00000454861.1	H3BNH8

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61780 AN: 151904 Hom.: 14894 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.567

Gnomad ASJ AF: 0.481

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.555

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.439

GnomAD4 exome AF: 0.514 AC: 40930 AN: 79638 Hom.: 11179 Cov.: 0 AF XY: 0.515 AC XY: 18857 AN XY: 36612

African (AFR) AF: 0.139 AC: 532 AN: 3824

American (AMR) AF: 0.586 AC: 1440 AN: 2458

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 2520 AN: 5034

East Asian (EAS) AF: 0.738 AC: 8246 AN: 11180

South Asian (SAS) AF: 0.545 AC: 373 AN: 684

European-Finnish (FIN) AF: 0.414 AC: 24 AN: 58

Middle Eastern (MID) AF: 0.450 AC: 218 AN: 484

European-Non Finnish (NFE) AF: 0.496 AC: 24410 AN: 49246

Other (OTH) AF: 0.475 AC: 3167 AN: 6670

GnomAD4 genome AF: 0.406 AC: 61784 AN: 152022 Hom.: 14892 Cov.: 32 AF XY: 0.410 AC XY: 30465 AN XY: 74300

African (AFR) AF: 0.142 AC: 5885 AN: 41470

American (AMR) AF: 0.567 AC: 8661 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.481 AC: 1667 AN: 3466

East Asian (EAS) AF: 0.670 AC: 3472 AN: 5180

South Asian (SAS) AF: 0.555 AC: 2680 AN: 4826

European-Finnish (FIN) AF: 0.412 AC: 4351 AN: 10554

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.494 AC: 33550 AN: 67940

Other (OTH) AF: 0.437 AC: 921 AN: 2106

Alfa AF: 0.274 Hom.: 698

Bravo AF: 0.410

Asia WGS AF: 0.568 AC: 1974 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	APC-Associated Polyposis Disorders (1)
-	-	-	Familial colorectal cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.4
DANN	Benign	0.42
PhyloP100		0.38
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: rs448475; hg19: chr5-112181379;