rs4705559

Positions:

• chr5-112714425-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001407446.1(APC):​c.165+6543A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 152,154 control chromosomes in the GnomAD database, including 14,908 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 0.41 (14908 hom., cov: 33)
• Consequence: APC NM_001407446.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.287

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_001127511.3	c.165+6543A>G		intron_variant
APC	NM_001354895.2	c.-19+6543A>G		intron_variant
APC	NM_001354897.2	c.165+6543A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000507379.6	c.165+6543A>G		intron_variant		2
APC	ENST00000509732.6	c.-19+6776A>G		intron_variant		4		P1
APC	ENST00000505350.2	c.165+6543A>G		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.405 AC: 61648 AN: 152036 Hom.: 14909 Cov.: 33

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.568

Gnomad ASJ AF: 0.481

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.442

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

GnomAD4 genome AF: 0.405 AC: 61651 AN: 152154 Hom.: 14908 Cov.: 33 AF XY: 0.408 AC XY: 30386 AN XY: 74388

Gnomad4 AFR AF: 0.137

Gnomad4 AMR AF: 0.568

Gnomad4 ASJ AF: 0.481

Gnomad4 EAS AF: 0.671

Gnomad4 SAS AF: 0.559

Gnomad4 FIN AF: 0.412

Gnomad4 NFE AF: 0.494

Gnomad4 OTH AF: 0.440

Alfa AF: 0.446 Hom.: 2828

Bravo AF: 0.408

Asia WGS AF: 0.576 AC: 2001 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.0
DANN	Benign	0.84

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4705559; hg19: chr5-112050122;