chr3-9475617-CT-C
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_001080517.3(SETD5):c.3856delT(p.Ser1286LeufsTer84) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001080517.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249238Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135204
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461712Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727138
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
This sequence change creates a premature translational stop signal (p.Ser1286Leufs*84) in the SETD5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 157 amino acid(s) of the SETD5 protein. This variant is present in population databases (no rsID available, gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with severe intellectual disability (PMID: 24680889). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 127106). This variant disrupts a region of the SETD5 protein in which other variant(s) (p.Ser1286Leufs*37) have been determined to be pathogenic (PMID: 28549204; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 157 amino acids are lost and replaced with 83 incorrect amino acids; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24680889) -
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Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency Pathogenic:2
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The c.3562del;p.(Ser1188Leufs*84) is a null frameshift variant in the SETD5 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript -PVS1_strong. This variant is not present in population databases (rs587777329, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is likely pathogenic. -
Inborn genetic diseases Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at