rs766151900

Positions:

• chr5-112707853-A-C
• chr5-112707853-A-G
• chr5-112707853-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001407446.1(APC):​c.136A>C​(p.Thr46Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000493 in 1,217,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: APC NM_001407446.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.413

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11718443).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_001407446.1	c.136A>C	p.Thr46Pro	missense_variant	1/16		NP_001394375.1
APC	NM_001354897.2	c.136A>C	p.Thr46Pro	missense_variant	1/15		NP_001341826.1
APC	NM_001127511.3	c.136A>C	p.Thr46Pro	missense_variant	1/14		NP_001120983.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000507379.6	c.136A>C	p.Thr46Pro	missense_variant	1/14	2		ENSP00000423224
APC	ENST00000509732.6	c.-19+204A>C		intron_variant		4		ENSP00000426541	P1
APC	ENST00000505350.2	c.136A>C	p.Thr46Pro	missense_variant, NMD_transcript_variant	1/16	3		ENSP00000481752

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000745 AC: 1 AN: 134162 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 73038

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000445

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000493 AC: 6 AN: 1217700 Hom.: 0 Cov.: 31 AF XY: 0.00000504 AC XY: 3 AN XY: 594864

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000781

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000567 AC: 1

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

May 13, 2020

This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 537610). 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. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of this non-coding change is currently unknown. While this variant is present in population databases (rs766151900), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	14
DANN	Benign	0.59
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.46	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.24
Sift	Benign	0.034	D
Sift4G	Uncertain	0.0070	D
MutPred		0.22		Loss of phosphorylation at T46 (P = 0.0217);
MVP		0.65
ClinPred		0.094	T
GERP RS		-1.1

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs766151900; hg19: chr5-112043550;