5-112839514-T-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_000038.6(APC):c.3920T>A(p.Ile1307Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,614,038 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,association,risk factor (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1307R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 28 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity; association; risk factor criteria provided, conflicting classifications P:21U:20B:1O:15

Conservation

PhyloP100: 0.887

Publications

352 publications found

Variant links:

COSMIC-nc: COSV57326270

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:

ENSG00000258864 (HGNC:):

ENSG00000258864 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007214457).

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00124 (1809/1461874) while in subpopulation MID AF = 0.022 (127/5768). AF 95% confidence interval is 0.0189. There are 28 homozygotes in GnomAdExome4. There are 954 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 28 AD,AR gene

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	HGVSp	Effect	Exon Rank	Protein	UniProt
APC	NM_000038.6	MANE Select	c.3920T>A	p.Ile1307Lys	missense	Exon 16 of 16	NP_000029.2
APC	NM_001407446.1		c.4004T>A	p.Ile1335Lys	missense	Exon 16 of 16	NP_001394375.1
APC	NM_001354896.2		c.3974T>A	p.Ile1325Lys	missense	Exon 17 of 17	NP_001341825.1	R4GMU6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APC	ENST00000257430.9	TSL:5 MANE Select	c.3920T>A	p.Ile1307Lys	missense	Exon 16 of 16	ENSP00000257430.4	P25054-1
APC	ENST00000508376.6	TSL:1	c.3920T>A	p.Ile1307Lys	missense	Exon 17 of 17	ENSP00000427089.2	P25054-1
APC	ENST00000502371.3	TSL:1	n.*2118T>A		non_coding_transcript_exon	Exon 12 of 12	ENSP00000484935.2	A0A087X2F3

Frequencies

GnomAD3 genomes

AF:

0.00128

AC:

194

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.0354

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000831

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00201

AC:

504

AN:

251040

AF XY:

0.00194

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.0361

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000688

Gnomad OTH exome

AF:

0.00327

GnomAD4 exome

AF:

0.00124

AC:

1809

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

954

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33478

American (AMR)

AF:

0.000581

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0370

AC:

966

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000510

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.0220

AC:

127

AN:

5768

European-Non Finnish (NFE)

AF:

0.000393

AC:

437

AN:

1112000

Other (OTH)

AF:

0.00334

AC:

202

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

131

262

393

524

655

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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

AF:

0.00126

AC:

191

AN:

152164

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41528

American (AMR)

AF:

0.000589

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0354

AC:

123

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000832

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000632

AC:

AN:

67986

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00314

Hom.:

Bravo

AF:

0.00136

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00169

AC:

205

EpiCase

AF:

0.00180

EpiControl

AF:

0.00119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity; association; risk factor

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (15)

Familial adenomatous polyposis 1 (15)

Colorectal cancer (6)

Hereditary cancer-predisposing syndrome (8)

Familial multiple polyposis syndrome (2)

not specified (3)

Breast carcinoma (1)

Diffuse midline glioma, H3 K27-altered (1)

APC-Associated Polyposis Disorders (1)

Breast cancer, susceptibility to (1)

Carcinoma of colon (1)

Colorectal cancer, susceptibility to (1)

FAMILIAL ADENOMATOUS POLYPOSIS 1, SUSCEPTIBILITY TO (1)

Familial colorectal cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Uncertain

0.45

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.60

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.0072

MetaSVM

Benign

-0.54

MutationAssessor

Benign

1.1

PhyloP100

0.89

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.080

REVEL

Benign

0.23

Sift

Benign

0.086

Sift4G

Benign

0.69

Polyphen

0.012

Vest4

0.21

MVP

0.88

ClinPred

0.0073

GERP RS

4.5

Varity_R

0.074

gMVP

0.64

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over