5-112707530-C-T

Variant names:

• chr5-112707530-C-T
• rs761454123
• NM_001407446.1:c.-188C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BP6

The NM_001407446.1(APC):​c.-188C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 487,828 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 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: APC NM_001407446.1 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.59
• 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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.15).
• BP6: Variant 5-112707530-C-T is Benign according to our data. Variant chr5-112707530-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 469858.

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.-188C>T		5_prime_UTR	Exon 1 of 16	NP_001394375.1
	APC	NM_001407447.1		c.-371C>T		5_prime_UTR	Exon 1 of 17	NP_001394376.1	R4GMU6
	APC	NM_001407448.1		c.-138C>T		5_prime_UTR	Exon 1 of 17	NP_001394377.1	R4GMU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000951167.1		c.-138C>T		5_prime_UTR	Exon 1 of 17	ENSP00000621226.1
	APC	ENST00000509732.6	TSL:4	c.-138C>T		5_prime_UTR	Exon 1 of 16	ENSP00000426541.2	P25054-1
	APC	ENST00000507379.6	TSL:2	c.-188C>T		5_prime_UTR	Exon 1 of 14	ENSP00000423224.2	P25054-3

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000238 AC: 8 AN: 335578 Hom.: 0 Cov.: 5 AF XY: 0.0000345 AC XY: 6 AN XY: 174006

African (AFR) AF: 0.00 AC: 0 AN: 10042

American (AMR) AF: 0.00 AC: 0 AN: 14952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10006

East Asian (EAS) AF: 0.00 AC: 0 AN: 19684

South Asian (SAS) AF: 0.00 AC: 0 AN: 46078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1596

European-Non Finnish (NFE) AF: 0.0000340 AC: 7 AN: 205932

Other (OTH) AF: 0.0000548 AC: 1 AN: 18240

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74386

African (AFR) AF: 0.0000482 AC: 2 AN: 41480

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

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)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	0.97
PhyloP100		1.6
PromoterAI		-0.52	Under-expression

Splicing

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

Other links and lift over

dbSNP: rs761454123; hg19: chr5-112043227;