rs730881228

Variant names:

• chr5-112819345-GTA-G
• rs730881228
• NM_000038.6:c.1312+3_1312+4delAT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000257430.9(APC):​c.1312+2_1312+3delTA variant causes a splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC ENST00000257430.9 splice_donor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.67

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112819345-GTA-G is Pathogenic according to our data. Variant chr5-112819345-GTA-G is described in ClinVar as [Pathogenic]. Clinvar id is 181775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.1312+3_1312+4delAT		splice_region_variant, intron_variant	Intron 10 of 15	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1312+2_1312+3delTA		splice_donor_variant, splice_region_variant, intron_variant	Intron 10 of 15	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:2

May 12, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a highly conserved nucleotide within the donor consensus splice site. This variant has not been published in the literature and is not present in population databases. ClinVar contains an entry for this variant (RCV000159517). While this particular variant has not been published in the literature, multiple substitutions involving the c.1312+3A have been reported to cause exon skipping and are considered pathogenic (PMID: 24599579, 8381580, 23159591, 17489848). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing indicate that this deletion abrogates the donor splice site for exon 10 of the APC gene. This is expected to disrupt splicing of the APC mRNA. For these reasons, this variant has been classified as Pathogenic. -

May 12, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been published in the literature, multiple substitutions involving the c.1312+3A have been reported to cause exon skipping and are considered pathogenic (PMID: 24599579, 8381580, 23159591, 17489848). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing indicate that this deletion abrogates the donor splice site for exon 10 of the APC gene. This is expected to disrupt splicing of the APC mRNA. This sequence change affects a highly conserved nucleotide within the donor consensus splice site. This variant has not been published in the literature and is not present in population databases. ClinVar contains an entry for this variant (RCV000159517). -

not provided Pathogenic:1

Aug 14, 2014

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This pathogenic variant is denoted APC c.1312+(3_4)delAT or IVS10+(3_4)delAT and consists of a deletion of two nucleotides at the +3 to +4 positions in intron 10 of the APC gene. The normal sequence, with the bases that are deleted in brackets, is AAgt[delat]gttc. Multiple in silico models predict this mutation to destroy the nearby natural splice donor site therefore causing abnormal gene splicing. The first adenine (A) nucleotide which is altered is conserved across species and the thymine (T) nucleotide is moderately conserved across species. APC c.1312+(3_4)delAT was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Although this variant has not been previously reported to our knowledge, multiple other mutations altering the same splice donor site including APC c.1312+3A>C, APC c.1312+3A>G, and APC c.1312+(3_6)delATGT, lead to aberrant splicing, have been reported in association with a Familial Adenomatous Polyposis (FAP)-associated syndrome, and are considered pathogenic (Nielsen 2007, Olschwang 1993, Aretz 2004, Kerr 2013, Wu 2001). The available information about APC c.1312+(3_4)delAT leads us to classify this mutation as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs730881228; hg19: chr5-112155042;