Variant 5-112707853-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001407446.1(APC):c.136A>C(p.Thr46Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000493 in 1,217,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

APC
NM_001407446.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.413

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11718443).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein
APC	NM_001407446.1 linkuse as main transcript	c.136A>C	p.Thr46Pro	missense_variant	1/16	NP_001394375.1
APC	NM_001354897.2 linkuse as main transcript	c.136A>C	p.Thr46Pro	missense_variant	1/15	NP_001341826.1
APC	NM_001127511.3 linkuse as main transcript	c.136A>C	p.Thr46Pro	missense_variant	1/14	NP_001120983.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	Appris
APC	ENST00000507379.6 linkuse as main transcript	c.136A>C	p.Thr46Pro	missense_variant	1/14	2	ENSP00000423224
APC	ENST00000509732.6 linkuse as main transcript	c.-19+204A>C		intron_variant		4	ENSP00000426541	P1
APC	ENST00000505350.2 linkuse as main transcript	c.136A>C	p.Thr46Pro	missense_variant, NMD_transcript_variant	1/16	3	ENSP00000481752

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000745

AC:

AN:

134162

Hom.:

AF XY:

0.00

AC XY:

AN XY:

73038

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000445

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000493

AC:

AN:

1217700

Hom.:

Cov.:

AF XY:

0.00000504

AC XY:

AN XY:

594864

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000781

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000567

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 13, 2020

This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID:¬†537610). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of this non-coding change is currently unknown. While this variant is present in population databases (rs766151900), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant occurs in a non-coding region of the APC gene. It does not change the encoded amino acid sequence of the APC protein. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.59

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.24

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.46

MutationTaster

Benign

1.0

PROVEAN

Benign

-2.0

REVEL

Benign

0.24

Sift

Benign

0.034

Sift4G

Uncertain

0.0070

MutPred

0.22

Loss of phosphorylation at T46 (P = 0.0217);

MVP

0.65

ClinPred

0.094

GERP RS

-1.1

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over