rs1486768673
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_004360.5(CDH1):c.100G>A(p.Ala34Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/21 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. A34S) has been classified as Uncertain significance.
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.100G>A | p.Ala34Thr | missense_variant | 2/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.100G>A | p.Ala34Thr | missense_variant | 2/15 | ||
CDH1 | NM_001317185.2 | c.-1516G>A | 5_prime_UTR_variant | 2/16 | |||
CDH1 | NM_001317186.2 | c.-1720G>A | 5_prime_UTR_variant | 2/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.100G>A | p.Ala34Thr | missense_variant | 2/16 | 1 | NM_004360.5 | P1 | |
CDH1 | ENST00000422392.6 | c.100G>A | p.Ala34Thr | missense_variant | 2/15 | 1 | |||
CDH1 | ENST00000566612.5 | c.100G>A | p.Ala34Thr | missense_variant, NMD_transcript_variant | 2/15 | 1 | |||
CDH1 | ENST00000566510.5 | c.100G>A | p.Ala34Thr | missense_variant, NMD_transcript_variant | 2/15 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 24AN: 141386Hom.: 0 Cov.: 32 FAILED QC
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000574 AC: 8AN: 1393956Hom.: 0 Cov.: 31 AF XY: 0.00000873 AC XY: 6AN XY: 687426
GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.000170 AC: 24AN: 141498Hom.: 0 Cov.: 32 AF XY: 0.000115 AC XY: 8AN XY: 69284
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CDH1 p.Ala34Thr variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, Cosmic, MutDB, Zhejiang University database, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Ala34 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 25, 2019 | This missense variant replaces alanine with threonine at codon 34 of the CDH1 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at