rs553525438
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The ENST00000261769.10(CDH1):c.1201G>A(p.Ala401Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. A401D) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.1201G>A | p.Ala401Thr | missense_variant | 9/16 | ENST00000261769.10 | NP_004351.1 | |
CDH1 | NM_001317185.2 | c.-415G>A | 5_prime_UTR_variant | 9/16 | NP_001304114.1 | |||
CDH1 | NM_001317186.2 | c.-619G>A | 5_prime_UTR_variant | 9/15 | NP_001304115.1 | |||
CDH1 | NM_001317184.2 | c.1137+1113G>A | intron_variant | NP_001304113.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.1201G>A | p.Ala401Thr | missense_variant | 9/16 | 1 | NM_004360.5 | ENSP00000261769 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251484Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135916
GnomAD4 exome Cov.: 32
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152278Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74464
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 16, 2021 | This missense variant replaces alanine with threonine at codon 401 of the CDH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251484 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 23, 2020 | The p.A401T variant (also known as c.1201G>A), located in coding exon 9 of the CDH1 gene, results from a G to A substitution at nucleotide position 1201. The alanine at codon 401 is replaced by threonine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Hereditary diffuse gastric adenocarcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 02, 2021 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 578436). 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 replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 401 of the CDH1 protein (p.Ala401Thr). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at