NM_001407446.1:c.-3C>A

Variant names:

• chr5-112707715-C-A
• rs771410311
• NM_001407446.1:c.-3C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001407446.1(APC):​c.-3C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene APC is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: APC NM_001407446.1 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.53
• Publications: 0 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

ACMG classification

Specifications for APC are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 5-112707715-C-A is Benign according to our data. Variant chr5-112707715-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 560803.

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.-3C>A		5_prime_UTR	Exon 1 of 16	NP_001394375.1
	APC	NM_001407447.1		c.-186C>A		5_prime_UTR	Exon 1 of 17	NP_001394376.1	R4GMU6
	APC	NM_001354897.2		c.-3C>A		5_prime_UTR	Exon 1 of 15	NP_001341826.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000507379.6	TSL:2	c.-3C>A		5_prime_UTR	Exon 1 of 14	ENSP00000423224.2	P25054-3
	APC	ENST00000951167.1		c.-19+66C>A		intron	N/A	ENSP00000621226.1
	APC	ENST00000509732.6	TSL:4	c.-19+66C>A		intron	N/A	ENSP00000426541.2	P25054-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1218372 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 595228

African (AFR) AF: 0.00 AC: 0 AN: 28304

American (AMR) AF: 0.00 AC: 0 AN: 30764

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21056

East Asian (EAS) AF: 0.00 AC: 0 AN: 24240

South Asian (SAS) AF: 0.00 AC: 0 AN: 76906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4894

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 970776

Other (OTH) AF: 0.00 AC: 0 AN: 48302

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.89
PhyloP100		1.5
PromoterAI		0.025	Neutral

Splicing

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

Other links and lift over

dbSNP: rs771410311; hg19: chr5-112043412;