chr5-112707585-C-G

Variant names:

• chr5-112707585-C-G
• rs79896135
• NM_001407446.1:c.-133C>G

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.-133C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 965,948 control chromosomes in the GnomAD database, including 9,920 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2037 hom., cov: 33)
  • Exomes 𝑓: 0.13 (7883 hom.)
• Consequence: APC NM_001407446.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.62
• Publications: 16 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 5-112707585-C-G is Benign according to our data. Variant chr5-112707585-C-G is described in ClinVar as Benign. ClinVar VariationId is 379246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_001407446.1	c.-133C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 16		NP_001394375.1
APC	NM_001407447.1	c.-316C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 17		NP_001394376.1
APC	NM_001407448.1	c.-83C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 17		NP_001394377.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000509732.6	c.-83C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 16	4		ENSP00000426541.2
APC	ENST00000507379.6	c.-133C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 14	2		ENSP00000423224.2
APC	ENST00000505350.2	n.-133C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 16	3		ENSP00000481752.1

Frequencies

GnomAD3 genomes AF: 0.158 AC: 23982 AN: 152128 Hom.: 2029 Cov.: 33

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.161

GnomAD4 exome AF: 0.134 AC: 108877 AN: 813702 Hom.: 7883 Cov.: 11 AF XY: 0.136 AC XY: 54542 AN XY: 401614

African (AFR) AF: 0.228 AC: 4536 AN: 19868

American (AMR) AF: 0.0797 AC: 1881 AN: 23592

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 1782 AN: 15226

East Asian (EAS) AF: 0.114 AC: 2447 AN: 21478

South Asian (SAS) AF: 0.176 AC: 10828 AN: 61584

European-Finnish (FIN) AF: 0.141 AC: 1541 AN: 10954

Middle Eastern (MID) AF: 0.174 AC: 599 AN: 3450

European-Non Finnish (NFE) AF: 0.129 AC: 80457 AN: 623392

Other (OTH) AF: 0.141 AC: 4806 AN: 34158

GnomAD4 genome AF: 0.158 AC: 24020 AN: 152246 Hom.: 2037 Cov.: 33 AF XY: 0.157 AC XY: 11682 AN XY: 74456

African (AFR) AF: 0.225 AC: 9334 AN: 41514

American (AMR) AF: 0.103 AC: 1577 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 387 AN: 3472

East Asian (EAS) AF: 0.136 AC: 702 AN: 5180

South Asian (SAS) AF: 0.174 AC: 843 AN: 4832

European-Finnish (FIN) AF: 0.126 AC: 1340 AN: 10610

Middle Eastern (MID) AF: 0.212 AC: 62 AN: 292

European-Non Finnish (NFE) AF: 0.137 AC: 9312 AN: 68012

Other (OTH) AF: 0.159 AC: 336 AN: 2112

Alfa AF: 0.0489 Hom.: 53

Bravo AF: 0.159

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 16, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Familial adenomatous polyposis 1 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.9
DANN	Benign	0.85
PhyloP100		-1.6
PromoterAI		-0.0034	Neutral
Mutation Taster		=299/1	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs79896135; hg19: chr5-112043282;