chr5-112845224-T-C

Variant names:

• chr5-112845224-T-C
• rs41116
• NM_000038.6:c.*1098T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001407446.1(APC):​c.*1098T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 232,296 control chromosomes in the GnomAD database, including 26,028 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.40 (14803 hom., cov: 32)
  • Exomes 𝑓: 0.51 (11225 hom.)
• Consequence: APC NM_001407446.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 1.33
• Publications: 21 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 5-112845224-T-C is Benign according to our data. Variant chr5-112845224-T-C is described in ClinVar as Benign. ClinVar VariationId is 83260.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407446.1. 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.*1098T>C		3_prime_UTR	Exon 16 of 16	NP_000029.2
	APC	NM_001407446.1		c.*1098T>C		3_prime_UTR	Exon 16 of 16	NP_001394375.1
	APC	NM_001354896.2		c.*1098T>C		3_prime_UTR	Exon 17 of 17	NP_001341825.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000257430.9	TSL:5 MANE Select	c.*1098T>C		3_prime_UTR	Exon 16 of 16	ENSP00000257430.4
	APC	ENST00000508376.6	TSL:1	c.*1098T>C		3_prime_UTR	Exon 17 of 17	ENSP00000427089.2
	ENSG00000258864	ENST00000520401.1	TSL:3	n.229-11425T>C		intron	N/A	ENSP00000454861.1

Frequencies

GnomAD3 genomes AF: 0.402 AC: 61122 AN: 151964 Hom.: 14805 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.566

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.440

GnomAD4 exome AF: 0.513 AC: 41126 AN: 80214 Hom.: 11225 Cov.: 0 AF XY: 0.513 AC XY: 18959 AN XY: 36942

African (AFR) AF: 0.123 AC: 469 AN: 3824

American (AMR) AF: 0.587 AC: 1458 AN: 2484

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 2532 AN: 5060

East Asian (EAS) AF: 0.739 AC: 8262 AN: 11182

South Asian (SAS) AF: 0.545 AC: 374 AN: 686

European-Finnish (FIN) AF: 0.442 AC: 212 AN: 480

Middle Eastern (MID) AF: 0.450 AC: 217 AN: 482

European-Non Finnish (NFE) AF: 0.495 AC: 24434 AN: 49320

Other (OTH) AF: 0.473 AC: 3168 AN: 6696

GnomAD4 genome AF: 0.402 AC: 61123 AN: 152082 Hom.: 14803 Cov.: 32 AF XY: 0.405 AC XY: 30138 AN XY: 74334

African (AFR) AF: 0.126 AC: 5245 AN: 41534

American (AMR) AF: 0.566 AC: 8644 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.482 AC: 1672 AN: 3470

East Asian (EAS) AF: 0.670 AC: 3457 AN: 5158

South Asian (SAS) AF: 0.555 AC: 2670 AN: 4810

European-Finnish (FIN) AF: 0.412 AC: 4356 AN: 10578

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.494 AC: 33556 AN: 67944

Other (OTH) AF: 0.438 AC: 926 AN: 2112

Alfa AF: 0.443 Hom.: 10768

Bravo AF: 0.405

Asia WGS AF: 0.568 AC: 1970 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	APC-Associated Polyposis Disorders (1)
-	-	-	Familial colorectal cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.8
DANN	Benign	0.78
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs41116; hg19: chr5-112180921; COSMIC: COSV57321664;