rs786205129
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024757.5(EHMT1):c.2877_2880del(p.Ser960GlyfsTer7) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L957L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_024757.5 frameshift, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EHMT1 | NM_024757.5 | c.2877_2880del | p.Ser960GlyfsTer7 | frameshift_variant, splice_region_variant | 20/27 | ENST00000460843.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EHMT1 | ENST00000460843.6 | c.2877_2880del | p.Ser960GlyfsTer7 | frameshift_variant, splice_region_variant | 20/27 | 5 | NM_024757.5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Kleefstra syndrome 1 Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. It is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic (ClinVar ID: VCV000065734/ PMID: 22670141). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 11, 2023 | This sequence change creates a premature translational stop signal (p.Ser960Glyfs*7) in the EHMT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EHMT1 are known to be pathogenic (PMID: 16826528, 19264732). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Kleefstra syndrome (PMID: 22670141). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 65734). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Mar 21, 2023 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Apr 18, 2022 | ACMG classification criteria: PVS1 very strong, PS4 supporting, PM2 moderated, PM6 moderated - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 25, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29276005, 22670141, 20945554, 31785789) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at