chr5-112780773-A-T

Variant names:

• chr5-112780773-A-T
• rs997606437
• NM_000038.6:c.532-17A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000038.6(APC):​c.532-17A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000546 in 1,539,040 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 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: APC NM_000038.6 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.187
• 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: 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-112780773-A-T is Benign according to our data. Variant chr5-112780773-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 371961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.532-17A>T		intron	N/A	NP_000029.2
	APC	NM_001407446.1		c.562-17A>T		intron	N/A	NP_001394375.1
	APC	NM_001354896.2		c.532-17A>T		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.532-17A>T		intron	N/A	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.532-17A>T		intron	N/A	ENSP00000427089.2	P25054-1
	APC	ENST00000502371.3	TSL:1	n.532-17A>T		intron	N/A	ENSP00000484935.2	A0A087X2F3

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151910 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.0000555 AC: 77 AN: 1387130 Hom.: 0 Cov.: 24 AF XY: 0.0000576 AC XY: 40 AN XY: 694176

African (AFR) AF: 0.0000319 AC: 1 AN: 31388

American (AMR) AF: 0.00 AC: 0 AN: 44332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25608

East Asian (EAS) AF: 0.00 AC: 0 AN: 38674

South Asian (SAS) AF: 0.00 AC: 0 AN: 83480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.0000707 AC: 74 AN: 1047152

Other (OTH) AF: 0.0000346 AC: 2 AN: 57820

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151910 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74212

African (AFR) AF: 0.00 AC: 0 AN: 41340

American (AMR) AF: 0.00 AC: 0 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67940

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Familial adenomatous polyposis 1 (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.36
DANN	Benign	0.44
PhyloP100		-0.19

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: rs997606437; hg19: chr5-112116470;