chr3-9475617-CT-C
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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
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
SETD5
NM_001080517.3 frameshift
NM_001080517.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.38
Genes affected
SETD5 (HGNC:25566): (SET domain containing 5) This function of this gene has yet to be determined but based on sequence similarity to other SET domain proteins it may function as a histone methyltransferase. Mutations in this gene have been associated with an autosomal dominant form of intellectual disability. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.109 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-9475617-CT-C is Pathogenic according to our data. Variant chr3-9475617-CT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127106.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3, Likely_pathogenic=1}. Variant chr3-9475617-CT-C is described in Lovd as [Pathogenic]. Variant chr3-9475617-CT-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249238Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135204
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461712Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727138
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 15, 2024 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 21, 2022 | 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) - |
Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | DASA | Feb 14, 2022 | 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. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 03, 2014 | - - |
Inborn genetic diseases Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 06, 2017 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at