rs138386816

Positions:

• chr5-112707566-C-T

Variant summary

Our verdict is Benign. Variant got -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 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.78

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 469844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112707566-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1109 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_001127511.3	c.-152C>T		5_prime_UTR_variant	1/14		NP_001120983.2
APC	NM_001354895.2	c.-335C>T		5_prime_UTR_variant	1/16		NP_001341824.1
APC	NM_001354897.2	c.-152C>T		5_prime_UTR_variant	1/15		NP_001341826.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000507379.6	c.-152C>T		5_prime_UTR_variant	1/14	2		ENSP00000423224
APC	ENST00000509732.6	c.-102C>T		5_prime_UTR_variant	1/16	4		ENSP00000426541	P1
APC	ENST00000505350.2	c.-152C>T		5_prime_UTR_variant, NMD_transcript_variant	1/16	3		ENSP00000481752

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

Gnomad4 AFR exome AF: 0.00115

Gnomad4 AMR exome AF: 0.00400

Gnomad4 ASJ exome AF: 0.000800

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00721

Gnomad4 FIN exome AF: 0.0173

Gnomad4 NFE exome AF: 0.00953

Gnomad4 OTH exome AF: 0.00571

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

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00673

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0101

Gnomad4 FIN AF: 0.0179

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00805 Hom.: 2

Bravo AF: 0.00592

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Familial adenomatous polyposis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

APC: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	0.99

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs138386816; hg19: chr5-112043263;