rs1312050427

chr5-112707880-C-Achr5-112707880-C-Gchr5-112707880-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q55H) has been classified 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, single submitter U:1
• Conservation: PhyloP100: 2.58

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19544974).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_001407446.1	c.163C>A	p.Gln55Lys	missense_variant, splice_region_variant	1/16
APC	NM_001354897.2	c.163C>A	p.Gln55Lys	missense_variant, splice_region_variant	1/15
APC	NM_001127511.3	c.163C>A	p.Gln55Lys	missense_variant, splice_region_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000507379.6	c.163C>A	p.Gln55Lys	missense_variant, splice_region_variant	1/14	2
APC	ENST00000509732.6	c.-19+231C>A		intron_variant		4		P1
APC	ENST00000505350.2	c.163C>A	p.Gln55Lys	missense_variant, splice_region_variant, NMD_transcript_variant	1/16	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000750 AC: 1 AN: 133360 Hom.: 0 AF XY: 0.0000138 AC XY: 1 AN XY: 72576

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: 17 AN: 1216266 Hom.: 0 Cov.: 31 AF XY: 0.00000673 AC XY: 4 AN XY: 594076

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.: 32

Bravo AF: 0.0000113

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

Invitae

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Uncertain	0.0
Cadd	Benign	22
Dann	Benign	0.92
Eigen	Benign	0.058
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	2.8	N
REVEL	Uncertain	0.39
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
MutPred		0.26		Gain of methylation at Q55 (P = 0.0099);
MVP		0.77
ClinPred		0.75	D
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

Other links and lift over

dbSNP: rs1312050427; hg19: chr5-112043577;