5-112707592-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001407446.1(APC):c.-126G>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 0.0000877 in 1,003,868 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

APC
NM_001407446.1 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.0220

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 5-112707592-G-T is Benign according to our data. Variant chr5-112707592-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 469827.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

BS2

High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons
APC	NM_001127511.3 linkuse as main transcript	c.-126G>T	5_prime_UTR_variant	1/14
APC	NM_001354895.2 linkuse as main transcript	c.-309G>T	5_prime_UTR_variant	1/16
APC	NM_001354897.2 linkuse as main transcript	c.-126G>T	5_prime_UTR_variant	1/15

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	Appris
APC	ENST00000507379.6 linkuse as main transcript	c.-126G>T	5_prime_UTR_variant	1/14	2
APC	ENST00000509732.6 linkuse as main transcript	c.-76G>T	5_prime_UTR_variant	1/16	4	P1
APC	ENST00000505350.2 linkuse as main transcript	c.-126G>T	5_prime_UTR_variant, NMD_transcript_variant	1/16	3

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151806

Hom.:

Cov.:

show subpopulations

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:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000736

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.0000916

AC:

AN:

851944

Hom.:

Cov.:

AF XY:

0.0000999

AC XY:

AN XY:

420228

show subpopulations

Gnomad4 AFR exome

AF:

0.0000483

Gnomad4 AMR exome

AF:

0.0000804

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000966

Gnomad4 SAS exome

AF:

0.0000475

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000101

Gnomad4 OTH exome

AF:

0.000113

GnomAD4 genome

AF:

0.0000658

AC:

AN:

151924

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000736

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.0000491

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 14, 2022

This variant, also known as NM_001127511.3:c.-126G>T, is located in the 5' untranslated region of an alternative transcript of the APC gene. To our knowledge, RNA expression studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Familial adenomatous polyposis 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 30, 2020

Has not been previously published as pathogenic or benign to our knowledge; No data available from control populations to assess the frequency of this variant -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

Cadd

Benign

8.7

Dann

Benign

0.80

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over