rs4705573

Variant names:

• chr5-112724927-T-C
• rs4705573
• NM_001407446.1:c.165+17045T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001407446.1(APC):​c.165+17045T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 152,056 control chromosomes in the GnomAD database, including 14,076 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.39 (14076 hom., cov: 31)
• Consequence: APC NM_001407446.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.523
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_001407446.1	c.165+17045T>C		intron_variant	Intron 1 of 15		NP_001394375.1
APC	NM_001407447.1	c.-19+17045T>C		intron_variant	Intron 1 of 16		NP_001394376.1
APC	NM_001407448.1	c.-19+17278T>C		intron_variant	Intron 1 of 16		NP_001394377.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000509732.6	c.-19+17278T>C		intron_variant	Intron 1 of 15	4		ENSP00000426541.2
APC	ENST00000507379.6	c.165+17045T>C		intron_variant	Intron 1 of 13	2		ENSP00000423224.2
APC	ENST00000505350.2	n.165+17045T>C		intron_variant	Intron 1 of 15	3		ENSP00000481752.1
APC	ENST00000713636.1	n.-19+17045T>C		intron_variant	Intron 1 of 16			ENSP00000518937.1

Frequencies

GnomAD3 genomes AF: 0.394 AC: 59884 AN: 151938 Hom.: 14076 Cov.: 31

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.492

Gnomad AMR AF: 0.556

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.668

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.430

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.394 AC: 59889 AN: 152056 Hom.: 14076 Cov.: 31 AF XY: 0.397 AC XY: 29528 AN XY: 74314

African (AFR) AF: 0.137 AC: 5667 AN: 41502

American (AMR) AF: 0.557 AC: 8513 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 1633 AN: 3468

East Asian (EAS) AF: 0.668 AC: 3446 AN: 5160

South Asian (SAS) AF: 0.553 AC: 2662 AN: 4816

European-Finnish (FIN) AF: 0.400 AC: 4215 AN: 10546

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.475 AC: 32271 AN: 67962

Other (OTH) AF: 0.429 AC: 904 AN: 2106

Alfa AF: 0.404 Hom.: 1826

Bravo AF: 0.397

Asia WGS AF: 0.574 AC: 1995 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.8
DANN	Benign	0.77
PhyloP100		0.52
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs4705573; hg19: chr5-112060624;