Genetic Variant APC:c.-132G>T (chr5-112707586-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001407446.1(APC):c.-132G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 970,022 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00099 ( 5 hom. )

Consequence

APC
NM_001407446.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.113

Publications

0 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 5-112707586-G-T is Benign according to our data. Variant chr5-112707586-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 469835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00142 (213/149642) while in subpopulation EAS AF = 0.0297 (154/5178). AF 95% confidence interval is 0.0259. There are 2 homozygotes in GnomAd4. There are 112 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407446.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
APC	NM_001407446.1	c.-132G>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_001394375.1
APC	NM_001407447.1	c.-315G>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_001394376.1	R4GMU6
APC	NM_001407448.1	c.-82G>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_001394377.1	R4GMU6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
APC	ENST00000951167.1		c.-82G>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	ENSP00000621226.1
APC	ENST00000509732.6	TSL:4	c.-82G>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000426541.2	P25054-1
APC	ENST00000507379.6	TSL:2	c.-132G>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	ENSP00000423224.2	P25054-3

Frequencies

GnomAD3 genomes

AF:

0.00142

AC:

213

AN:

149522

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000655

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000333

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0295

Gnomad SAS

AF:

0.00107

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000272

Gnomad OTH

AF:

0.00243

GnomAD4 exome

AF:

0.000989

AC:

811

AN:

820380

Hom.:

Cov.:

AF XY:

0.000990

AC XY:

401

AN XY:

405170

show subpopulations

African (AFR)

AF:

0.000300

AC:

AN:

20022

American (AMR)

AF:

0.000170

AC:

AN:

23478

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15258

East Asian (EAS)

AF:

0.0228

AC:

488

AN:

21374

South Asian (SAS)

AF:

0.00100

AC:

AN:

61970

European-Finnish (FIN)

AF:

0.0000910

AC:

AN:

10990

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3520

European-Non Finnish (NFE)

AF:

0.000278

AC:

175

AN:

629352

Other (OTH)

AF:

0.00218

AC:

AN:

34416

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

123

164

205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00142

AC:

213

AN:

149642

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

112

AN XY:

73246

show subpopulations

African (AFR)

AF:

0.000653

AC:

AN:

41374

American (AMR)

AF:

0.000332

AC:

AN:

15054

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3422

East Asian (EAS)

AF:

0.0297

AC:

154

AN:

5178

South Asian (SAS)

AF:

0.000854

AC:

AN:

4684

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.000272

AC:

AN:

66134

Other (OTH)

AF:

0.00241

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.0000531

Hom.:

Bravo

AF:

0.00186

Asia WGS

AF:

0.0120

AC:

AN:

3470

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

APC-related disorder (1)

Familial adenomatous polyposis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.3

(source)

DANN

Benign

0.85

PhyloP100

0.11

PromoterAI

-0.096

Neutral

(source)

Mutation Taster

=299/1

polymorphism

(source)

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over