rs606231203
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_002354.3(EPCAM):c.491+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.0000181 in 1,602,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
EPCAM
NM_002354.3 splice_donor
NM_002354.3 splice_donor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.33
Genes affected
EPCAM (HGNC:11529): (epithelial cell adhesion molecule) This gene encodes a carcinoma-associated antigen and is a member of a family that includes at least two type I membrane proteins. This antigen is expressed on most normal epithelial cells and gastrointestinal carcinomas and functions as a homotypic calcium-independent cell adhesion molecule. The antigen is being used as a target for immunotherapy treatment of human carcinomas. Mutations in this gene result in congenital tufting enteropathy. [provided by RefSeq, Dec 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06878307 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-47375300-G-A is Pathogenic according to our data. Variant chr2-47375300-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12771.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47375300-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
EPCAM | NM_002354.3 | c.491+1G>A | splice_donor_variant | ENST00000263735.9 | NP_002345.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EPCAM | ENST00000263735.9 | c.491+1G>A | splice_donor_variant | 1 | NM_002354.3 | ENSP00000263735 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152174Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251214Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135780
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GnomAD4 exome AF: 0.0000179 AC: 26AN: 1450332Hom.: 0 Cov.: 27 AF XY: 0.0000208 AC XY: 15AN XY: 722384
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74334
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Congenital diarrhea 5 with tufting enteropathy Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2013 | - - |
Gastric cancer Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 06, 2021 | The c.491+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 4 of the EPCAM gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function. Based on data from gnomAD, the A allele has an overall frequency of 0.0056% (14/251,214) total alleles studied. The highest observed frequency was 0.03% (11/34,570) of Latino alleles. This alteration was reported homozygous or compound heterozygous with a second mutation in EPCAM in multiple patients with failure to thrive, diarrhea, vomiting, and endoscopic duodenal biopsies with characteristic histology consistent with congenital tufting enteropathy (Sivagnanam, 2008; Ko, 2010; Fang, 2020). This nucleotide position is highly conserved in available vertebrate species. Reverse-transcription polymerase chain reaction of duodenal tissue demonstrated a novel alternative splice form with deletion of exon 4 (Sivagnanam, 2008). Mutant mice with universal Epcam exon 4 deletion showed widespread epithelial dysplasia, intestinal failure, and limited life spans with a dramatic lack of weight gain compared with wildtype mice (Mueller, 2014). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at