5-112775612-TAAA-TAAAA

Variant names:

• chr5-112775612-T-TA
• rs730881230
• NM_000038.6:c.423-4dupA

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_000038.6(APC):​c.423-4dupA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0514 in 1,091,404 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.059 (0 hom.)
• Consequence: APC NM_000038.6 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.937
• Publications: 4 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant 5-112775612-T-TA is Benign according to our data. Variant chr5-112775612-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 802132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00151 (217/143732) while in subpopulation EAS AF = 0.00738 (37/5012). AF 95% confidence interval is 0.00551. There are 1 homozygotes in GnomAd4. There are 116 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.423-4dupA		splice_region intron	N/A	NP_000029.2
	APC	NM_001407446.1		c.453-4dupA		splice_region intron	N/A	NP_001394375.1
	APC	NM_001354896.2		c.423-4dupA		splice_region intron	N/A	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.423-17_423-16insA		intron	N/A	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.423-17_423-16insA		intron	N/A	ENSP00000427089.2	P25054-1
	APC	ENST00000502371.3	TSL:1	n.423-17_423-16insA		intron	N/A	ENSP00000484935.2	A0A087X2F3

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 217 AN: 143672 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00258

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00736

Gnomad SAS AF: 0.00437

Gnomad FIN AF: 0.00106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000826

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0409 AC: 4146 AN: 101416 AF XY: 0.0392

Gnomad AFR exome AF: 0.0363

Gnomad AMR exome AF: 0.0600

Gnomad ASJ exome AF: 0.0500

Gnomad EAS exome AF: 0.0554

Gnomad FIN exome AF: 0.0256

Gnomad NFE exome AF: 0.0346

Gnomad OTH exome AF: 0.0530

GnomAD4 exome AF: 0.0589 AC: 55865 AN: 947672 Hom.: 0 Cov.: 0 AF XY: 0.0571 AC XY: 27041 AN XY: 473928

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0504 AC: 1140 AN: 22632

American (AMR) AF: 0.0401 AC: 1237 AN: 30862

Ashkenazi Jewish (ASJ) AF: 0.0498 AC: 875 AN: 17568

East Asian (EAS) AF: 0.0520 AC: 1384 AN: 26634

South Asian (SAS) AF: 0.0474 AC: 2748 AN: 57942

European-Finnish (FIN) AF: 0.0339 AC: 1235 AN: 36410

Middle Eastern (MID) AF: 0.0415 AC: 155 AN: 3732

European-Non Finnish (NFE) AF: 0.0630 AC: 44846 AN: 712324

Other (OTH) AF: 0.0567 AC: 2245 AN: 39568

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00151 AC: 217 AN: 143732 Hom.: 1 Cov.: 32 AF XY: 0.00166 AC XY: 116 AN XY: 69738

African (AFR) AF: 0.00152 AC: 60 AN: 39502

American (AMR) AF: 0.00258 AC: 37 AN: 14368

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3350

East Asian (EAS) AF: 0.00738 AC: 37 AN: 5012

South Asian (SAS) AF: 0.00438 AC: 20 AN: 4562

European-Finnish (FIN) AF: 0.00106 AC: 9 AN: 8468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.000826 AC: 54 AN: 65338

Other (OTH) AF: 0.00 AC: 0 AN: 1974

Alfa AF: 0.0246 Hom.: 1

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	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 (2)
-	-	1	Familial adenomatous polyposis 1 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.94
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs730881230; hg19: chr5-112111309; COSMIC: COSV104378972; COSMIC: COSV104378972;