rs864622070
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The ENST00000261769.10(CDH1):c.1615A>G(p.Thr539Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T539I) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000261769.10 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.1615A>G | p.Thr539Ala | missense_variant | 11/16 | ENST00000261769.10 | NP_004351.1 | |
CDH1 | NM_001317184.2 | c.1432A>G | p.Thr478Ala | missense_variant | 10/15 | NP_001304113.1 | ||
CDH1 | NM_001317185.2 | c.67A>G | p.Thr23Ala | missense_variant | 11/16 | NP_001304114.1 | ||
CDH1 | NM_001317186.2 | c.-254-2672A>G | intron_variant | NP_001304115.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.1615A>G | p.Thr539Ala | missense_variant | 11/16 | 1 | NM_004360.5 | ENSP00000261769 | P1 | |
ENST00000563916.1 | n.264-3670T>C | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461870Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727238
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 20, 2023 | An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 539 of the CDH1 protein (p.Thr539Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 219399). 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 24, 2022 | The p.T539A variant (also known as c.1615A>G), located in coding exon 11 of the CDH1 gene, results from an A to G substitution at nucleotide position 1615. The threonine at codon 539 is replaced by alanine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at