Variant rs1057517567 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001407446.1(APC):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,370,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 8.2e-7 ( 0 hom. )

Consequence

APC
NM_001407446.1 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.45

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:

APC (HGNC:):

APC links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein	UniProt
APC	NM_001407446.1 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	1/16	NP_001394375.1
APC	NM_001354897.2 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	1/15	NP_001341826.1
APC	NM_001127511.3 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	1/14	NP_001120983.2	P25054-3Q4LE70

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
APC	ENST00000507379.6 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	1/14	2	ENSP00000423224.2	A0A2Q2SV78
APC	ENST00000509732.6 linkuse as main transcript	c.-19+71G>A		intron_variant		4	ENSP00000426541.2	D6RFL6
APC	ENST00000505350.2 linkuse as main transcript	n.3G>A		non_coding_transcript_exon_variant	1/16	3	ENSP00000481752.1	A0A087WYF3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

8.21e-7

AC:

AN:

1218380

Hom.:

Cov.:

AF XY:

0.00000168

AC XY:

AN XY:

595230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000103

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 12, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This variant occurs in a non-coding region of the APC gene. It does not change the encoded amino acid sequence of the APC protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 371850). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

DANN

Uncertain

0.99

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.90

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.73

PROVEAN

Benign

-0.060

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

MutPred

0.90

Gain of sheet (P = 0.039);

MVP

0.90

ClinPred

0.97

GERP RS

4.0

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