rs77551834

Variant names:

• chr5-112822783-A-T
• rs77551834
• NM_000038.6:c.1408+792A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000038.6(APC):​c.1408+792A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0054 in 152,218 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene APC is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.0054 (18 hom., cov: 32)
• Consequence: APC NM_000038.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.453
• 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: Genomics England PanelApp, G2P
• familial adenomatous polyposis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), 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

ACMG classification

Specifications for APC are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 5-112822783-A-T is Benign according to our data. Variant chr5-112822783-A-T is described in ClinVar as Benign. ClinVar VariationId is 82574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0731 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.1408+792A>T		intron	N/A	NP_000029.2
	APC	NM_001407446.1		c.1439-524A>T		intron	N/A	NP_001394375.1
	APC	NM_001354896.2		c.1409-524A>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.1408+792A>T		intron	N/A	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.1408+792A>T		intron	N/A	ENSP00000427089.2	P25054-1
	APC	ENST00000502371.3	TSL:1	n.1408+792A>T		intron	N/A	ENSP00000484935.2	A0A087X2F3

Frequencies

GnomAD3 genomes AF: 0.00538 AC: 819 AN: 152100 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00454

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0791

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.00573

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00540 AC: 822 AN: 152218 Hom.: 18 Cov.: 32 AF XY: 0.00548 AC XY: 408 AN XY: 74430

African (AFR) AF: 0.00462 AC: 192 AN: 41520

American (AMR) AF: 0.00170 AC: 26 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.0795 AC: 412 AN: 5184

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4824

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00228 AC: 155 AN: 68000

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00445 Hom.: 0

Bravo AF: 0.00583

Asia WGS AF: 0.0240 AC: 82 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Familial adenomatous polyposis 1 (1)
-	-	1	not specified (1)
-	-	-	Familial colorectal cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.1
DANN	Benign	0.57
PhyloP100		-0.45
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs77551834;

hg19: chr5-112158480;