Genetic Variant APC:c.423-5_423-4dupAA (chr5-112775612-T-TAA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000038.6(APC):c.423-5_423-4dupAA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

APC
NM_000038.6 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.937

Publications

4 publications found

Variant links:

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: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
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

APC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000038.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
APC	NM_000038.6	MANE Select	c.423-5_423-4dupAA	splice_region intron	N/A	NP_000029.2
APC	NM_001407446.1		c.453-5_453-4dupAA	splice_region intron	N/A	NP_001394375.1
APC	NM_001354896.2		c.423-5_423-4dupAA	splice_region intron	N/A	NP_001341825.1	R4GMU6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
APC	ENST00000257430.9	TSL:5 MANE Select	c.423-17_423-16insAA	intron	N/A	ENSP00000257430.4	P25054-1
APC	ENST00000508376.6	TSL:1	c.423-17_423-16insAA	intron	N/A	ENSP00000427089.2	P25054-1
APC	ENST00000502371.3	TSL:1	n.423-17_423-16insAA	intron	N/A	ENSP00000484935.2	A0A087X2F3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

143738

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000187

AC:

AN:

101416

AF XY:

0.000221

show subpopulations

Gnomad AFR exome

AF:

0.000139

Gnomad AMR exome

AF:

0.000371

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000138

Gnomad FIN exome

AF:

0.000211

Gnomad NFE exome

AF:

0.000174

Gnomad OTH exome

AF:

0.000411

GnomAD4 exome

AF:

0.000225

AC:

231

AN:

1025050

Hom.:

Cov.:

AF XY:

0.000214

AC XY:

110

AN XY:

514686

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000248

AC:

AN:

24174

American (AMR)

AF:

0.000212

AC:

AN:

33096

Ashkenazi Jewish (ASJ)

AF:

0.0000511

AC:

AN:

19582

East Asian (EAS)

AF:

0.0000333

AC:

AN:

30020

South Asian (SAS)

AF:

0.000238

AC:

AN:

63138

European-Finnish (FIN)

AF:

0.0000991

AC:

AN:

40356

Middle Eastern (MID)

AF:

0.000251

AC:

AN:

3992

European-Non Finnish (NFE)

AF:

0.000240

AC:

184

AN:

767552

Other (OTH)

AF:

0.000278

AC:

AN:

43140

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.238

Heterozygous variant carriers

119

159

199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

143738

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69692

African (AFR)

AF:

0.00

AC:

AN:

39422

American (AMR)

AF:

0.00

AC:

AN:

14352

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3352

East Asian (EAS)

AF:

0.00

AC:

AN:

5024

South Asian (SAS)

AF:

0.00

AC:

AN:

4574

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8490

Middle Eastern (MID)

AF:

0.00

AC:

AN:

298

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65386

Other (OTH)

AF:

0.00

AC:

AN:

1956

Alfa

AF:

0.000720

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.94

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over