chr7-66991238-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5
The NM_016038.4(SBDS):c.523C>T(p.Arg175Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R175Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_016038.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SBDS | NM_016038.4 | c.523C>T | p.Arg175Trp | missense_variant | 4/5 | ENST00000246868.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SBDS | ENST00000246868.7 | c.523C>T | p.Arg175Trp | missense_variant | 4/5 | 1 | NM_016038.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152076Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251392Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135892
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461736Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727172
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152076Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74258
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 09, 2023 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies are inconclusive regarding whether or not R175W effects the stability or fold of the SBDS protein (Erdos et al., 2006; Finch et al., 2011); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 17350924, 17046571, 21536732, 34758064, 17916435) - |
Aplastic anemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 18, 2022 | - - |
Aplastic anemia;C4692625:Shwachman-Diamond syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Aug 16, 2021 | SBDS NM_016038.2 exon 4 p.Arg175Trp (c.523C>T): This variant has been reported in the literature in 1 individual with Schwachman-Diamond Syndrome who also carried an additional variant in the same gene (Erdos 2007 PMID:17350924). It is present in 0.001% (1/68032) European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/7-66991238-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:418467). A nuclear magnetic resonance (NMR) spectroscopy study of the mutant protein suggests that this variant alters the protein's structural and chemical properties (Finch 2011 PMID:21536732). However, this may not result in an impact to in vivo biological function. Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at