chr5-112775653-C-G

Position:

• chr5-112775653-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1 PM2 PM5 BP4_Strong

The NM_000038.6(APC):​c.447C>G​(p.Asp149Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D149V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a helix (size 37) in uniprot entity APC_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000038.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-112775652-A-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.067240775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.447C>G	p.Asp149Glu	missense_variant	5/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.447C>G	p.Asp149Glu	missense_variant	5/16	5	NM_000038.6	ENSP00000257430	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 02, 2019

This variant has not been reported in the literature in individuals with APC-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with glutamic acid at codon 149 of the APC protein (p.Asp149Glu). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Benign	0.67
DEOGEN2	Benign	0.36	.;T;T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.80	T;.;T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.067	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.42	.;N;N;.
MutationTaster	Benign	0.96	N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	1.1	N;N;N;N
REVEL	Benign	0.24
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.27, 0.28
MutPred		0.17		.;Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);
MVP		0.48
ClinPred		0.14	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.055

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs750821213; hg19: chr5-112111350;