5-112844078-C-A

Variant names:

• chr5-112844078-C-A
• rs864622473
• NM_000038.6:c.8484C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_000038.6(APC):​c.8484C>A​(p.Thr2828Thr) variant causes a synonymous 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. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. T2828T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.754
• Publications: 0 publications found

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]

APC Gene-Disease associations (from GenCC):

• classic or attenuated familial adenomatous polyposis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• desmoid tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• familial adenomatous polyposis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• APC-related attenuated familial adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Turcot syndrome with polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000258864 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 5-112844078-C-A is Benign according to our data. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-112844078-C-A is described in CliVar as Likely_benign. Clinvar id is 1763549.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.754 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.8484C>A	p.Thr2828Thr	synonymous_variant	Exon 16 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.8484C>A	p.Thr2828Thr	synonymous_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.229-12571C>A		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:1

Jul 23, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	1.1
DANN	Benign	0.76
PhyloP100		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs864622473; hg19: chr5-112179775;