rs190326008

Variant names:

• chr5-112707477-A-C
• rs190326008
• NM_001407446.1:c.-241A>C

Your query was ambiguous. Multiple possible variants found:

• chr5-112707477-A-C
• chr5-112707477-A-G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001407446.1(APC):​c.-241A>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000477 in 419,574 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: APC NM_001407446.1 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.19
• 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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-112707477-A-C is Benign according to our data. Variant chr5-112707477-A-C is described in ClinVar as Benign. ClinVar VariationId is 469867.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	NM_001407446.1		c.-241A>C		upstream_gene	N/A	NP_001394375.1
	APC	NM_001407447.1		c.-424A>C		upstream_gene	N/A	NP_001394376.1
	APC	NM_001407448.1		c.-191A>C		upstream_gene	N/A	NP_001394377.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000509732.6	TSL:4	c.-191A>C		upstream_gene	N/A	ENSP00000426541.2
	APC	ENST00000507379.6	TSL:2	c.-241A>C		upstream_gene	N/A	ENSP00000423224.2
	APC	ENST00000505350.2	TSL:3	n.-241A>C		upstream_gene	N/A	ENSP00000481752.1

Frequencies

GnomAD3 genomes AF: 0.00000670 AC: 1 AN: 149182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000370 AC: 1 AN: 270392 Hom.: 0 Cov.: 2 AF XY: 0.00 AC XY: 0 AN XY: 140454

African (AFR) AF: 0.00 AC: 0 AN: 8056

American (AMR) AF: 0.00 AC: 0 AN: 12714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9222

East Asian (EAS) AF: 0.00 AC: 0 AN: 18638

South Asian (SAS) AF: 0.00 AC: 0 AN: 40800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1126

European-Non Finnish (NFE) AF: 0.00000643 AC: 1 AN: 155516

Other (OTH) AF: 0.00 AC: 0 AN: 15768

GnomAD4 genome AF: 0.00000670 AC: 1 AN: 149182 Hom.: 0 Cov.: 33 AF XY: 0.0000137 AC XY: 1 AN XY: 72896

African (AFR) AF: 0.00 AC: 0 AN: 38574

American (AMR) AF: 0.00 AC: 0 AN: 15156

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: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2052

Alfa AF: 0.00 Hom.: 1

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Familial adenomatous polyposis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.62
DANN	Benign	0.46
PhyloP100		-1.2
PromoterAI		-0.044	Neutral

Splicing

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

Other links and lift over

dbSNP: rs190326008; hg19: chr5-112043174;