5-112775612-T-A

Variant names:

• chr5-112775612-T-A
• rs534684461
• NM_000038.6:c.423-17T>A

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.423-17T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,171,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: APC NM_000038.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.00
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet, 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-A is Benign according to our data. Variant chr5-112775612-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 217981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00112 (161/143788) while in subpopulation AFR AF = 0.00266 (105/39506). AF 95% confidence interval is 0.00225. There are 0 homozygotes in GnomAd4. There are 84 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.423-17T>A		intron	N/A	NP_000029.2
	APC	NM_001407446.1		c.453-17T>A		intron	N/A	NP_001394375.1
	APC	NM_001354896.2		c.423-17T>A		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.423-17T>A		intron	N/A	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.423-17T>A		intron	N/A	ENSP00000427089.2	P25054-1
	APC	ENST00000502371.3	TSL:1	n.423-17T>A		intron	N/A	ENSP00000484935.2	A0A087X2F3

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 161 AN: 143726 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000906

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000597

Gnomad SAS AF: 0.00219

Gnomad FIN AF: 0.000236

Gnomad MID AF: 0.00336

Gnomad NFE AF: 0.000398

Gnomad OTH AF: 0.000511

GnomAD2 exomes AF: 0.00146 AC: 148 AN: 101416 AF XY: 0.00151

Gnomad AFR exome AF: 0.00444

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.000500

Gnomad EAS exome AF: 0.00151

Gnomad FIN exome AF: 0.000421

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.000821

GnomAD4 exome AF: 0.00103 AC: 1057 AN: 1027318 Hom.: 0 Cov.: 20 AF XY: 0.00103 AC XY: 532 AN XY: 515782

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

African (AFR) AF: 0.00322 AC: 78 AN: 24196

American (AMR) AF: 0.000784 AC: 26 AN: 33182

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 9 AN: 19614

East Asian (EAS) AF: 0.000832 AC: 25 AN: 30066

South Asian (SAS) AF: 0.00177 AC: 112 AN: 63240

European-Finnish (FIN) AF: 0.000223 AC: 9 AN: 40424

Middle Eastern (MID) AF: 0.00125 AC: 5 AN: 3994

European-Non Finnish (NFE) AF: 0.000981 AC: 755 AN: 769372

Other (OTH) AF: 0.000879 AC: 38 AN: 43230

⚠️ 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: 0.00112 AC: 161 AN: 143788 Hom.: 0 Cov.: 32 AF XY: 0.00120 AC XY: 84 AN XY: 69758

African (AFR) AF: 0.00266 AC: 105 AN: 39506

American (AMR) AF: 0.000905 AC: 13 AN: 14370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3352

East Asian (EAS) AF: 0.000599 AC: 3 AN: 5012

South Asian (SAS) AF: 0.00219 AC: 10 AN: 4562

European-Finnish (FIN) AF: 0.000236 AC: 2 AN: 8480

Middle Eastern (MID) AF: 0.00365 AC: 1 AN: 274

European-Non Finnish (NFE) AF: 0.000398 AC: 26 AN: 65374

Other (OTH) AF: 0.000507 AC: 1 AN: 1974

Alfa AF: 0.00152 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.6
DANN	Benign	0.32
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.22		Position offset: 17

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

Other links and lift over

dbSNP: rs534684461; hg19: chr5-112111309; COSMIC: COSV57326839; COSMIC: COSV57326839;