Genetic Variant NM_000038.6:c.3949G>C (chr5-112839543-G-C) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000038.6(APC):c.3949G>C(p.Glu1317Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00727 in 1,614,214 control chromosomes in the GnomAD database, including 60 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1317G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0055 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0075 ( 54 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:26O:2

Conservation

PhyloP100: 4.69

Publications

123 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: 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

APC links:

ENSG00000258864 (HGNC:):

ENSG00000258864 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 38 uncertain in NM_000038.6

BP4

Computational evidence support a benign effect (MetaRNN=0.00723657).

BP6

Variant 5-112839543-G-C is Benign according to our data. Variant chr5-112839543-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00554 (844/152344) while in subpopulation NFE AF = 0.00739 (503/68028). AF 95% confidence interval is 0.00686. There are 6 homozygotes in GnomAd4. There are 363 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 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
APC	NM_000038.6	MANE Select	c.3949G>C	p.Glu1317Gln	missense	Exon 16 of 16	NP_000029.2
APC	NM_001407446.1		c.4033G>C	p.Glu1345Gln	missense	Exon 16 of 16	NP_001394375.1
APC	NM_001354896.2		c.4003G>C	p.Glu1335Gln	missense	Exon 17 of 17	NP_001341825.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
APC	ENST00000257430.9	TSL:5 MANE Select	c.3949G>C	p.Glu1317Gln	missense	Exon 16 of 16	ENSP00000257430.4
APC	ENST00000508376.6	TSL:1	c.3949G>C	p.Glu1317Gln	missense	Exon 17 of 17	ENSP00000427089.2
APC	ENST00000502371.3	TSL:1	n.*2147G>C		non_coding_transcript_exon	Exon 12 of 12	ENSP00000484935.2

Frequencies

GnomAD3 genomes

AF:

0.00554

AC:

843

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00574

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00739

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00438

AC:

1101

AN:

251162

AF XY:

0.00443

show subpopulations

Gnomad AFR exome

AF:

0.00523

Gnomad AMR exome

AF:

0.00402

Gnomad ASJ exome

AF:

0.00507

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.00646

Gnomad OTH exome

AF:

0.00604

GnomAD4 exome

AF:

0.00745

AC:

10894

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00720

AC XY:

5236

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00618

AC:

207

AN:

33478

American (AMR)

AF:

0.00391

AC:

175

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00520

AC:

136

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00197

AC:

170

AN:

86256

European-Finnish (FIN)

AF:

0.000431

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.0120

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00863

AC:

9592

AN:

1111998

Other (OTH)

AF:

0.00864

AC:

522

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

691

1382

2074

2765

3456

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

386

772

1158

1544

1930

<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:

0.00554

AC:

844

AN:

152344

Hom.:

Cov.:

AF XY:

0.00487

AC XY:

363

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00575

AC:

239

AN:

41578

American (AMR)

AF:

0.00379

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00249

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00739

AC:

503

AN:

68028

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

125

166

208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00688

Hom.:

Bravo

AF:

0.00597

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00636

AC:

ESP6500EA

AF:

0.00930

AC:

ExAC

AF:

0.00413

AC:

501

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00736

EpiControl

AF:

0.00640

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial adenomatous polyposis 1 (8)

not provided (6)

not specified (7)

Hereditary cancer-predisposing syndrome (5)

APC-Associated Polyposis Disorders (1)

Carcinoma of colon (1)

Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.56

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.052

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.70

M_CAP

Benign

0.043

MetaRNN

Benign

0.0072

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.2

PhyloP100

4.7

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.7

REVEL

Benign

0.21

Sift

Benign

0.15

Sift4G

Benign

0.11

Polyphen

0.0010

Vest4

0.14

MVP

0.76

ClinPred

0.022

GERP RS

5.2

Varity_R

0.12

gMVP

0.39

Mutation Taster

=92/8

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