rs75580617

Variant names:

• chr5-112707473-A-C
• rs75580617
• NM_001407446.1:c.-245A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001407446.1(APC):​c.-245A>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0393 in 417,264 control chromosomes in the GnomAD database, including 681 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (329 hom., cov: 33)
  • Exomes 𝑓: 0.035 (352 hom.)
• Consequence: APC NM_001407446.1 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0670
• Publications: 9 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet, 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-112707473-A-C is Benign according to our data. Variant chr5-112707473-A-C is described in ClinVar as Benign. ClinVar VariationId is 379248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407446.1. 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_001407446.1		c.-245A>C		upstream_gene	N/A	NP_001394375.1
	APC	NM_001407447.1		c.-428A>C		upstream_gene	N/A	NP_001394376.1	R4GMU6
	APC	NM_001407448.1		c.-195A>C		upstream_gene	N/A	NP_001394377.1	R4GMU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000951167.1		c.-195A>C		upstream_gene	N/A	ENSP00000621226.1
	APC	ENST00000509732.6	TSL:4	c.-195A>C		upstream_gene	N/A	ENSP00000426541.2	P25054-1
	APC	ENST00000507379.6	TSL:2	c.-245A>C		upstream_gene	N/A	ENSP00000423224.2	P25054-3

Frequencies

GnomAD3 genomes AF: 0.0472 AC: 7180 AN: 152174 Hom.: 328 Cov.: 33

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0237

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.0697

Gnomad FIN AF: 0.00489

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0592

GnomAD4 exome AF: 0.0348 AC: 9219 AN: 264972 Hom.: 352 Cov.: 2 AF XY: 0.0367 AC XY: 5040 AN XY: 137444

African (AFR) AF: 0.104 AC: 886 AN: 8500

American (AMR) AF: 0.0207 AC: 259 AN: 12534

Ashkenazi Jewish (ASJ) AF: 0.0341 AC: 310 AN: 9102

East Asian (EAS) AF: 0.111 AC: 2036 AN: 18354

South Asian (SAS) AF: 0.0616 AC: 2444 AN: 39692

European-Finnish (FIN) AF: 0.00698 AC: 59 AN: 8454

Middle Eastern (MID) AF: 0.0516 AC: 56 AN: 1086

European-Non Finnish (NFE) AF: 0.0173 AC: 2625 AN: 151676

Other (OTH) AF: 0.0349 AC: 544 AN: 15574

GnomAD4 genome AF: 0.0472 AC: 7187 AN: 152292 Hom.: 329 Cov.: 33 AF XY: 0.0476 AC XY: 3542 AN XY: 74472

African (AFR) AF: 0.104 AC: 4316 AN: 41514

American (AMR) AF: 0.0236 AC: 362 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3472

East Asian (EAS) AF: 0.134 AC: 697 AN: 5186

South Asian (SAS) AF: 0.0695 AC: 336 AN: 4832

European-Finnish (FIN) AF: 0.00489 AC: 52 AN: 10626

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0173 AC: 1180 AN: 68032

Other (OTH) AF: 0.0586 AC: 124 AN: 2116

Alfa AF: 0.0425 Hom.: 85

Bravo AF: 0.0519

Asia WGS AF: 0.112 AC: 388 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Familial adenomatous polyposis 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.0
DANN	Benign	0.71
PhyloP100		0.067
PromoterAI		0.027	Neutral

Splicing

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

Other links and lift over

dbSNP: rs75580617; hg19: chr5-112043170; COSMIC: COSV71820291;