rs41115

Variant names:

• chr5-112840073-G-A
• rs41115
• NM_000038.6:c.4479G>A

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.4479G>A​(p.Thr1493Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 1,613,660 control chromosomes in the GnomAD database, including 318,158 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. T1493T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.60 (27967 hom., cov: 31)
  • Exomes 𝑓: 0.63 (290191 hom.)
• Consequence: APC NM_000038.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: 0.0920
• Publications: 114 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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 5-112840073-G-A is Benign according to our data. Variant chr5-112840073-G-A is described in ClinVar as Benign. ClinVar VariationId is 42242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.092 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.4479G>A	p.Thr1493Thr	synonymous	Exon 16 of 16	NP_000029.2
	APC	NM_001407446.1		c.4563G>A	p.Thr1521Thr	synonymous	Exon 16 of 16	NP_001394375.1
	APC	NM_001354896.2		c.4533G>A	p.Thr1511Thr	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.4479G>A	p.Thr1493Thr	synonymous	Exon 16 of 16	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.4479G>A	p.Thr1493Thr	synonymous	Exon 17 of 17	ENSP00000427089.2	P25054-1
	APC	ENST00000508624.5	TSL:1	n.*3801G>A		non_coding_transcript_exon	Exon 17 of 17	ENSP00000424265.1	E7EMH9

Frequencies

GnomAD3 genomes AF: 0.602 AC: 91324 AN: 151810 Hom.: 27950 Cov.: 31

Gnomad AFR AF: 0.534

Gnomad AMI AF: 0.617

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.567

Gnomad EAS AF: 0.820

Gnomad SAS AF: 0.731

Gnomad FIN AF: 0.537

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.613

Gnomad OTH AF: 0.612

GnomAD2 exomes AF: 0.650 AC: 162664 AN: 250358 AF XY: 0.649

Gnomad AFR exome AF: 0.533

Gnomad AMR exome AF: 0.734

Gnomad ASJ exome AF: 0.582

Gnomad EAS exome AF: 0.822

Gnomad FIN exome AF: 0.559

Gnomad NFE exome AF: 0.619

Gnomad OTH exome AF: 0.651

GnomAD4 exome AF: 0.627 AC: 917207 AN: 1461732 Hom.: 290191 Cov.: 63 AF XY: 0.629 AC XY: 457710 AN XY: 727164

African (AFR) AF: 0.520 AC: 17411 AN: 33466

American (AMR) AF: 0.727 AC: 32481 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 15209 AN: 26132

East Asian (EAS) AF: 0.840 AC: 33361 AN: 39700

South Asian (SAS) AF: 0.709 AC: 61156 AN: 86250

European-Finnish (FIN) AF: 0.573 AC: 30594 AN: 53414

Middle Eastern (MID) AF: 0.614 AC: 3540 AN: 5768

European-Non Finnish (NFE) AF: 0.616 AC: 685244 AN: 1111914

Other (OTH) AF: 0.633 AC: 38211 AN: 60388

GnomAD4 genome AF: 0.602 AC: 91393 AN: 151928 Hom.: 27967 Cov.: 31 AF XY: 0.603 AC XY: 44806 AN XY: 74264

African (AFR) AF: 0.535 AC: 22134 AN: 41406

American (AMR) AF: 0.669 AC: 10221 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 1969 AN: 3470

East Asian (EAS) AF: 0.820 AC: 4247 AN: 5182

South Asian (SAS) AF: 0.731 AC: 3517 AN: 4814

European-Finnish (FIN) AF: 0.537 AC: 5646 AN: 10520

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

European-Non Finnish (NFE) AF: 0.613 AC: 41624 AN: 67946

Other (OTH) AF: 0.610 AC: 1289 AN: 2114

Alfa AF: 0.611 Hom.: 45518

Bravo AF: 0.610

Asia WGS AF: 0.753 AC: 2615 AN: 3476

EpiCase AF: 0.610

EpiControl AF: 0.612

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)
-	-	1	Gastric cancer;C0346629:Colorectal cancer;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1;C4749917:Gastric adenocarcinoma and proximal polyposis of the stomach (1)
-	-	-	Familial colorectal cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	2.6
DANN	Benign	0.77
PhyloP100		0.092
Mutation Taster		=92/8	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: rs41115; hg19: chr5-112175770; COSMIC: COSV57321403; COSMIC: COSV57321403;