rs1554076217

Positions:

• chr5-112801381-C-G
• chr5-112801381-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_000038.6(APC):​c.832C>G​(p.Gln278Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q278H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense, splice_region
• Scores: Splicing: ADA: 0.8513
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.75

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-112801383-G-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.35641658).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.832C>G	p.Gln278Glu	missense_variant, splice_region_variant	8/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.832C>G	p.Gln278Glu	missense_variant, splice_region_variant	8/16	5	NM_000038.6	ENSP00000257430	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	.;T;T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.80	T;.;T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.4	.;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.66	N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.066	T;T;T;T
Sift4G	Benign	0.50	T;T;T;T
Polyphen		0.92	.;P;P;.
Vest4		0.79, 0.68
MutPred		0.20		.;Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);
MVP		0.83
ClinPred		0.76	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.85
dbscSNV1_RF	Benign	0.56
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.62		Position offset: -3

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-112137078;