rs373597944
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePP3_Strong
The NM_002354.3(EPCAM):c.426-1G>A variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000106 in 1,603,194 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
EPCAM
NM_002354.3 splice_acceptor
NM_002354.3 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.16
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 variant, 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.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EPCAM | NM_002354.3 | c.426-1G>A | splice_acceptor_variant | ENST00000263735.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EPCAM | ENST00000263735.9 | c.426-1G>A | splice_acceptor_variant | 1 | NM_002354.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152148Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251198Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135792
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GnomAD4 exome AF: 0.00000965 AC: 14AN: 1451046Hom.: 0 Cov.: 29 AF XY: 0.0000125 AC XY: 9AN XY: 722534
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Congenital diarrhea 5 with tufting enteropathy Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2013 | - - |
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 16, 2017 | Variant summary: The EPCAM c.426-1G>A variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a significant impact on normal splicing, which has been shown to occur via Western blot (see Schnell_HMG_2013 below), although this has not been corroborated by RNA studies. This variant was found in the large control database ExAC at a frequency of 0.0000167 (2/119674 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic EPCAM variant (0.0000284). The variant has been identified in at least 1 homozygous patient diagnosed with congenital tufting enteropathy (CTE)(SIVAGNANAM_Gastro_2008), but has not been associated with Lynch syndrome phenotypes in the literature. A functional analysis showed that the variant, which was predicted to cause a deletion of ~20 amino acids that verified by Western blot, impairs proper localization of EPCAM to the plasma membrane (Schnell_HMG_2013). However, the role of this dysfunction in Lynch syndrome development was not established. In addition, two submissions to ClinVar have classified this variant with conflicting interpretations including uncertain significance and pathogenic, though both were submitted under the condition of CTE. Although there is evidence that the variant is deleterious in the context of CTE, there is no data regarding whether the variant is involved in Lynch syndrome phenotype manifestations or not. As such, this variant is classified as VUS specifically in the context of an inherited predisposition to cancers including Lynch syndrome. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
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_AL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at