chr5-112707880-C-A

Position:

chr5-112707880-C-A

Variant summary

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

The NM_001407446.1(APC):c.163C>A(p.Gln55Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000014 in 1,216,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

APC
NM_001407446.1 missense, splice_region

Scores

Splicing: ADA: 0.002944

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.58

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:

APC (HGNC:):

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=0.19544974).

BS2

High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein
APC	NM_001407446.1 linkuse as main transcript	c.163C>A	p.Gln55Lys	missense_variant, splice_region_variant	1/16	NP_001394375.1
APC	NM_001407447.1 linkuse as main transcript	c.-21C>A		splice_region_variant	1/17	NP_001394376.1
APC	NM_001354897.2 linkuse as main transcript	c.163C>A	p.Gln55Lys	missense_variant, splice_region_variant	1/15	NP_001341826.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
APC	ENST00000507379.6 linkuse as main transcript	c.163C>A	p.Gln55Lys	missense_variant, splice_region_variant	1/14	2	ENSP00000423224.2	A0A2Q2SV78
APC	ENST00000509732.6 linkuse as main transcript	c.-19+231C>A		intron_variant		4	ENSP00000426541.2	D6RFL6
APC	ENST00000505350.2 linkuse as main transcript	n.163C>A		splice_region_variant, non_coding_transcript_exon_variant	1/16	3	ENSP00000481752.1	A0A087WYF3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000750

AC:

AN:

133360

Hom.:

AF XY:

0.0000138

AC XY:

AN XY:

72576

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000410

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000140

AC:

AN:

1216266

Hom.:

Cov.:

AF XY:

0.00000673

AC XY:

AN XY:

594076

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000978

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000521

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000722

Gnomad4 OTH exome

AF:

0.0000623

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

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. This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 537613). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Benign

0.92

Eigen

Benign

0.058

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.61

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.60

PROVEAN

Benign

2.8

REVEL

Uncertain

0.39

Sift

Benign

1.0

Sift4G

Benign

1.0

MutPred

0.26

Gain of methylation at Q55 (P = 0.0099);

MVP

0.77

ClinPred

0.75

GERP RS

4.2

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0029

dbscSNV1_RF

Benign

0.032

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