chr19-50479052-CG-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_206538.4(EMC10):c.287delG(p.Gly96AlafsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,605,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_206538.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152122Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000254 AC: 6AN: 236018Hom.: 0 AF XY: 0.0000312 AC XY: 4AN XY: 128080
GnomAD4 exome AF: 0.0000158 AC: 23AN: 1453752Hom.: 0 Cov.: 31 AF XY: 0.0000166 AC XY: 12AN XY: 722628
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152122Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74328
ClinVar
Submissions by phenotype
Neurodevelopmental disorder with dysmorphic facies and variable seizures Pathogenic:4Uncertain:1
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PVS1, PM3_VeryStrong, PM2 -
The detected change is listed in gnomAD with a frequency of 0.002542% (6/236018) (as of May 12, 2022). It is not reported in the dbSNP database (dbSNP150, as of May 12, 2022). The change has already been described in the literature as a recurrent variant in patients with developmental disorders and dysmorphism (Shao et al., 2021; Umair et al., 2020). In the case of stop or nonsense variants in a gene matching the phenotype, there is also a high probability of pathogenetic relevance. Based on the current state of knowledge, the variant can be classified as a pathogenic variant (ACMG criteria). -
This frameshifting variant in exon 3 of 7 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been previously reported as a homozygous change in individuals with Neurodevelopmental disorder with dysmorphic facies and variable seizures (NEDDFAS) (PMID: 33531666, 35684946). The c.287del (p.Gly96AlafsTer9) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (6/236018) and is absent in the homozygous state; thus it is presumed to be rare. Based on the available evidence, the c.287del (p.Gly96AlafsTer9) variant is classified as Pathogenic. -
Intellectual disability Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at