rs42427

Variant names:

• chr5-112840628-G-A
• rs42427
• NM_000038.6:c.5034G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-112840628-G-A
• chr5-112840628-G-T
• chr5-112840628-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000038.6(APC):​c.5034G>A​(p.Gly1678Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 1,613,474 control chromosomes in the GnomAD database, including 322,713 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G1678G) has been classified as Likely benign. The gene APC is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.60 (28272 hom., cov: 32)
  • Exomes 𝑓: 0.63 (294441 hom.)
• Consequence: APC NM_000038.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: 0.493
• Publications: 78 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: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• 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

Specifications for APC are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-112840628-G-A is Benign according to our data. Variant chr5-112840628-G-A is described in ClinVar as Benign. ClinVar VariationId is 42243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.493 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000038.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	NM_000038.6	MANE Select	c.5034G>A	p.Gly1678Gly	synonymous	Exon 16 of 16	NP_000029.2
	APC	NM_001407446.1		c.5118G>A	p.Gly1706Gly	synonymous	Exon 16 of 16	NP_001394375.1
	APC	NM_001354896.2		c.5088G>A	p.Gly1696Gly	synonymous	Exon 17 of 17	NP_001341825.1	R4GMU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000257430.9	TSL:5 MANE Select	c.5034G>A	p.Gly1678Gly	synonymous	Exon 16 of 16	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.5034G>A	p.Gly1678Gly	synonymous	Exon 17 of 17	ENSP00000427089.2	P25054-1
	APC	ENST00000508624.5	TSL:1	n.*4356G>A		non_coding_transcript_exon	Exon 17 of 17	ENSP00000424265.1	E7EMH9

Frequencies

GnomAD3 genomes AF: 0.605 AC: 91862 AN: 151912 Hom.: 28255 Cov.: 32

Gnomad AFR AF: 0.536

Gnomad AMI AF: 0.614

Gnomad AMR AF: 0.674

Gnomad ASJ AF: 0.567

Gnomad EAS AF: 0.820

Gnomad SAS AF: 0.730

Gnomad FIN AF: 0.537

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.618

Gnomad OTH AF: 0.614

GnomAD2 exomes AF: 0.652 AC: 163051 AN: 249920 AF XY: 0.652

Gnomad AFR exome AF: 0.535

Gnomad AMR exome AF: 0.736

Gnomad ASJ exome AF: 0.582

Gnomad EAS exome AF: 0.822

Gnomad FIN exome AF: 0.560

Gnomad NFE exome AF: 0.623

Gnomad OTH exome AF: 0.655

GnomAD4 exome AF: 0.632 AC: 923861 AN: 1461444 Hom.: 294441 Cov.: 58 AF XY: 0.634 AC XY: 460903 AN XY: 727040

African (AFR) AF: 0.522 AC: 17467 AN: 33470

American (AMR) AF: 0.729 AC: 32591 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 15219 AN: 26128

East Asian (EAS) AF: 0.840 AC: 33345 AN: 39682

South Asian (SAS) AF: 0.709 AC: 61169 AN: 86246

European-Finnish (FIN) AF: 0.574 AC: 30634 AN: 53372

Middle Eastern (MID) AF: 0.616 AC: 3548 AN: 5764

European-Non Finnish (NFE) AF: 0.622 AC: 691474 AN: 1111706

Other (OTH) AF: 0.636 AC: 38414 AN: 60376

GnomAD4 genome AF: 0.605 AC: 91931 AN: 152030 Hom.: 28272 Cov.: 32 AF XY: 0.606 AC XY: 45044 AN XY: 74326

African (AFR) AF: 0.536 AC: 22230 AN: 41466

American (AMR) AF: 0.674 AC: 10307 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 1966 AN: 3466

East Asian (EAS) AF: 0.820 AC: 4232 AN: 5164

South Asian (SAS) AF: 0.730 AC: 3524 AN: 4826

European-Finnish (FIN) AF: 0.537 AC: 5677 AN: 10572

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.618 AC: 41959 AN: 67940

Other (OTH) AF: 0.612 AC: 1291 AN: 2110

Alfa AF: 0.616 Hom.: 50386

Bravo AF: 0.613

Asia WGS AF: 0.754 AC: 2616 AN: 3476

EpiCase AF: 0.613

EpiControl AF: 0.618

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	2	Familial adenomatous polyposis 1 (2)
-	-	2	not provided (2)
-	-	1	APC-Associated Polyposis Disorders (1)
-	-	1	Carcinoma of colon (1)
-	-	-	Familial colorectal cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.0
DANN	Benign	0.77
PhyloP100		0.49
Mutation Taster		=80/20	polymorphism

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: rs42427; hg19: chr5-112176325; COSMIC: COSV57321627; COSMIC: COSV57321627;