5-112707842-G-C

Variant names:

• chr5-112707842-G-C
• rs1057517570
• NM_001407446.1:c.125G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001407446.1(APC):​c.125G>C​(p.Gly42Ala) 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. 9/14 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. G42D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_001407446.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.09

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.123426646).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_001407446.1	c.125G>C	p.Gly42Ala	missense_variant	Exon 1 of 16		NP_001394375.1
APC	NM_001354897.2	c.125G>C	p.Gly42Ala	missense_variant	Exon 1 of 15		NP_001341826.1
APC	NM_001127511.3	c.125G>C	p.Gly42Ala	missense_variant	Exon 1 of 14		NP_001120983.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000507379.6	c.125G>C	p.Gly42Ala	missense_variant	Exon 1 of 14	2		ENSP00000423224.2
APC	ENST00000509732.6	c.-19+193G>C		intron_variant	Intron 1 of 15	4		ENSP00000426541.2
APC	ENST00000505350.2	n.125G>C		non_coding_transcript_exon_variant	Exon 1 of 16	3		ENSP00000481752.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

May 02, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies and prediction algorithms are not available for this variant, and the functional significance of this non-coding change 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. 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 has not been reported in the literature in individuals with APC-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	15
DANN	Uncertain	0.99
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	-0.26	T
PhyloP100		2.1
PROVEAN	Benign	0.92	N
REVEL	Benign	0.19
Sift	Benign	0.071	T
Sift4G	Benign	0.15	T
MutPred		0.23		Loss of sheet (P = 0.0315);
MVP		0.79
ClinPred		0.12	T
GERP RS		2.2
PromoterAI		0.0019	Neutral
Mutation Taster		=296/4	polymorphism

Splicing

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

Publications

Loading publications...

Other links and lift over

dbSNP: rs1057517570; hg19: chr5-112043539;