5-112707418-A-G

Variant names:

• chr5-112707418-A-G
• rs372923973
• NM_001407446.1:c.-300A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001407446.1(APC):​c.-300A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000258 in 387,612 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: APC NM_001407446.1 upstream_gene
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.977
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 5-112707418-A-G is Benign according to our data. Variant chr5-112707418-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 469878.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.-300A>G		upstream_gene	N/A	NP_001394375.1
	APC	NM_001407447.1		c.-483A>G		upstream_gene	N/A	NP_001394376.1
	APC	NM_001407448.1		c.-250A>G		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.-250A>G		upstream_gene	N/A	ENSP00000426541.2
	APC	ENST00000507379.6	TSL:2	c.-300A>G		upstream_gene	N/A	ENSP00000423224.2
	APC	ENST00000505350.2	TSL:3	n.-300A>G		upstream_gene	N/A	ENSP00000481752.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152292 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000340 AC: 8 AN: 235320 Hom.: 0 AF XY: 0.00000827 AC XY: 1 AN XY: 120904

African (AFR) AF: 0.00 AC: 0 AN: 7924

American (AMR) AF: 0.00 AC: 0 AN: 10816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8374

East Asian (EAS) AF: 0.00 AC: 0 AN: 17362

South Asian (SAS) AF: 0.00 AC: 0 AN: 33216

European-Finnish (FIN) AF: 0.000126 AC: 1 AN: 7906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1050

European-Non Finnish (NFE) AF: 0.0000372 AC: 5 AN: 134488

Other (OTH) AF: 0.000141 AC: 2 AN: 14184

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74406

African (AFR) AF: 0.00 AC: 0 AN: 41484

American (AMR) AF: 0.00 AC: 0 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

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

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: 0.0000294 AC: 2 AN: 68056

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions as Germline

Significance: Likely 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	-0.71
CADD	Benign	0.66
DANN	Benign	0.80
PhyloP100		-0.98
PromoterAI		0.00060	Neutral

Splicing

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

Other links and lift over

dbSNP: rs372923973; hg19: chr5-112043115;