5-112707592-G-C

Variant names:

• chr5-112707592-G-C
• rs948080320
• NM_001407446.1:c.-126G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001407446.1(APC):​c.-126G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000697 in 1,003,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000059 (0 hom.)
• Consequence: APC NM_001407446.1 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.0220
• 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: 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 5-112707592-G-C is Benign according to our data. Variant chr5-112707592-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 537576.

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.-126G>C		5_prime_UTR	Exon 1 of 16	NP_001394375.1
	APC	NM_001407447.1		c.-309G>C		5_prime_UTR	Exon 1 of 17	NP_001394376.1
	APC	NM_001407448.1		c.-76G>C		5_prime_UTR	Exon 1 of 17	NP_001394377.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000951167.1		c.-76G>C		5_prime_UTR	Exon 1 of 17	ENSP00000621226.1
	APC	ENST00000509732.6	TSL:4	c.-76G>C		5_prime_UTR	Exon 1 of 16	ENSP00000426541.2
	APC	ENST00000507379.6	TSL:2	c.-126G>C		5_prime_UTR	Exon 1 of 14	ENSP00000423224.2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151806 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000587 AC: 5 AN: 851944 Hom.: 0 Cov.: 12 AF XY: 0.00000714 AC XY: 3 AN XY: 420228

African (AFR) AF: 0.0000483 AC: 1 AN: 20702

American (AMR) AF: 0.00 AC: 0 AN: 24886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15936

East Asian (EAS) AF: 0.0000966 AC: 2 AN: 20698

South Asian (SAS) AF: 0.00 AC: 0 AN: 63144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3688

European-Non Finnish (NFE) AF: 0.00000305 AC: 2 AN: 656400

Other (OTH) AF: 0.00 AC: 0 AN: 35310

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151806 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74158

African (AFR) AF: 0.0000242 AC: 1 AN: 41346

American (AMR) AF: 0.0000656 AC: 1 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5094

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67922

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Familial adenomatous polyposis 1 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	9.1
DANN	Benign	0.73
PhyloP100		0.022
PromoterAI		-0.43	Neutral

Splicing

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

Other links and lift over

dbSNP: rs948080320; hg19: chr5-112043289;