rs749591910
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_004360.5(CDH1):c.48G>A(p.Gln16=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CDH1
NM_004360.5 splice_region, synonymous
NM_004360.5 splice_region, synonymous
Scores
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 3.02
Genes affected
CDH1 (HGNC:1748): (cadherin 1) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 16-68737463-G-A is Pathogenic according to our data. Variant chr16-68737463-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 574809.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| CDH1 | NM_004360.5 | c.48G>A | p.Gln16= | splice_region_variant, synonymous_variant | 1/16 | ENST00000261769.10 | |
| CDH1 | NM_001317184.2 | c.48G>A | p.Gln16= | splice_region_variant, synonymous_variant | 1/15 | ||
| CDH1 | NM_001317185.2 | c.-1568G>A | splice_region_variant, 5_prime_UTR_variant | 1/16 | |||
| CDH1 | NM_001317186.2 | c.-1772G>A | splice_region_variant, 5_prime_UTR_variant | 1/15 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CDH1 | ENST00000261769.10 | c.48G>A | p.Gln16= | splice_region_variant, synonymous_variant | 1/16 | 1 | NM_004360.5 | P1 | |
| CDH1 | ENST00000422392.6 | c.48G>A | p.Gln16= | splice_region_variant, synonymous_variant | 1/15 | 1 | |||
| CDH1 | ENST00000566612.5 | c.48G>A | p.Gln16= | splice_region_variant, synonymous_variant, NMD_transcript_variant | 1/15 | 1 | |||
| CDH1 | ENST00000566510.5 | c.48G>A | p.Gln16= | splice_region_variant, synonymous_variant, NMD_transcript_variant | 1/15 | 5 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1385322Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 684252
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1385322
Hom.:
Cov.:
30
AF XY:
AC XY:
0
AN XY:
684252
Gnomad4 AFR exome
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GnomAD4 genome
GnomAD4 genome
Cov.:
33
Bravo
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Pathogenic:1Uncertain:1
| Pathogenic, criteria provided, single submitter | clinical testing | European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto | Aug 01, 2022 | PVS1_Moderate; PS3; PS4_Supporting; PM2; PP1_Supporting (PMID: 30311375) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 06, 2022 | 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). RNA analysis performed to evaluate the impact of this variant on mRNA splicing indicates it does not significantly alter splicing (Invitae). ClinVar contains an entry for this variant (Variation ID: 574809). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 16 of the CDH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CDH1 protein. This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -4
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at