5-112707566-C-T

Variant names:

• chr5-112707566-C-T
• rs138386816
• NM_001407446.1:c.-152C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BS1 BS2

The NM_001407446.1(APC):​c.-152C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00814 in 758,894 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0084 (30 hom.)
• Consequence: APC NM_001407446.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.78
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.11).
• BP6: Variant 5-112707566-C-T is Benign according to our data. Variant chr5-112707566-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 469844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00728 (1109/152356) while in subpopulation SAS AF = 0.0101 (49/4832). AF 95% confidence interval is 0.00949. There are 6 homozygotes in GnomAd4. There are 543 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

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_001407446.1		c.-152C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_001394375.1
	APC	NM_001407447.1		c.-335C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_001394376.1	R4GMU6
	APC	NM_001407448.1		c.-102C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_001394377.1	R4GMU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000951167.1		c.-102C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	ENSP00000621226.1
	APC	ENST00000509732.6	TSL:4	c.-102C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000426541.2	P25054-1
	APC	ENST00000507379.6	TSL:2	c.-152C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	ENSP00000423224.2	P25054-3

Frequencies

GnomAD3 genomes AF: 0.00730 AC: 1112 AN: 152238 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0105

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.00835 AC: 5066 AN: 606538 Hom.: 30 Cov.: 8 AF XY: 0.00824 AC XY: 2503 AN XY: 303924

African (AFR) AF: 0.00115 AC: 18 AN: 15586

American (AMR) AF: 0.00400 AC: 76 AN: 18982

Ashkenazi Jewish (ASJ) AF: 0.000800 AC: 10 AN: 12494

East Asian (EAS) AF: 0.00 AC: 0 AN: 20724

South Asian (SAS) AF: 0.00721 AC: 391 AN: 54242

European-Finnish (FIN) AF: 0.0173 AC: 171 AN: 9868

Middle Eastern (MID) AF: 0.00225 AC: 6 AN: 2662

European-Non Finnish (NFE) AF: 0.00953 AC: 4238 AN: 444674

Other (OTH) AF: 0.00571 AC: 156 AN: 27306

GnomAD4 genome AF: 0.00728 AC: 1109 AN: 152356 Hom.: 6 Cov.: 33 AF XY: 0.00729 AC XY: 543 AN XY: 74490

African (AFR) AF: 0.00149 AC: 62 AN: 41586

American (AMR) AF: 0.00673 AC: 103 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0101 AC: 49 AN: 4832

European-Finnish (FIN) AF: 0.0179 AC: 190 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0101 AC: 688 AN: 68028

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00805 Hom.: 2

Bravo AF: 0.00592

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Classic or attenuated familial adenomatous polyposis (1)
-	-	1	Familial adenomatous polyposis 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	0.99
PhyloP100		2.8
PromoterAI		-0.51	Under-expression
Mutation Taster		=181/119	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs138386816; hg19: chr5-112043263;