7-66995297-TC-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_016038.4(SBDS):c.120del(p.Ser41AlafsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,204 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
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SBDS
NM_016038.4 frameshift
NM_016038.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.597
Genes affected
SBDS (HGNC:19440): (SBDS ribosome maturation factor) This gene encodes a highly conserved protein that plays an essential role in ribosome biogenesis. The encoded protein interacts with elongation factor-like GTPase 1 to disassociate eukaryotic initiation factor 6 from the late cytoplasmic pre-60S ribosomal subunit allowing assembly of the 80S subunit. Mutations within this gene are associated with the autosomal recessive disorder Shwachman-Bodian-Diamond syndrome. This gene has a closely linked pseudogene that is distally located. [provided by RefSeq, Jan 2017]
TYW1 (HGNC:25598): (tRNA-yW synthesizing protein 1 homolog) Wybutosine (yW) is a hypermodified guanosine found in phenylalanine tRNA adjacent to the anticodon that stabilizes codon-anticodon interactions in the ribosome. In yeast, the homolog of this gene is essential for the synthesis of wybutosine. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 7-66995297-TC-T is Pathogenic according to our data. Variant chr7-66995297-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 265256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-66995297-TC-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SBDS | NM_016038.4 | c.120del | p.Ser41AlafsTer18 | frameshift_variant | 1/5 | ENST00000246868.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SBDS | ENST00000246868.7 | c.120del | p.Ser41AlafsTer18 | frameshift_variant | 1/5 | 1 | NM_016038.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251248Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135864
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000411 AC: 6AN: 1461448Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727024
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 07, 2016 | The c.120delG pathogenic variant in the SBDS gene has been reported previously (as c.119delG due to alternate nomenclature) in association with Schwachman-Diamond syndrome (Boocock et al., 2003). The c.120delG variant causes a frameshift starting with codon Serine 41, changes this amino acid to an Alanine residue and creates a premature Stop codon at position 18 of the new reading frame, denoted p.Ser41AlafsX18. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.120delG variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.120delG as a pathogenic variant. - |
Pathogenic, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 13, 2022 | DNA sequence analysis of the SBDS gene demonstrated a one base pair deletion in exon 1, c.120del. This sequence change results in an amino acid frameshift and creates a premature stop codon 18 amino acids downstream of the change, p.Ser41Alafs*18. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated SBDS protein with potentially abnormal function. This sequence change has been described in the gnomAD database in 2 individual which corresponds to a population frequency of 0.0008% ((dbSNP rs1175585213). This pathogenic sequence change has previously been described in individuals with SBDS-related disorders (PMID: 12496757, 24388329). Homozygous or compound heterozygous pathogenic variants in the SBDS gene are associated with Shwachman-Bodian-Diamond Syndrome (SBDS) [OMIM#260400]. Features of SDS include exocrine pancreatic dysfunction, growth failure, skeletal changes and hematologic abnormalities with susceptibility to myelodysplastic syndrome and acute myelogeneous leukemia. One pathogenic variant, c.258+2T>G, has been identified in individuals with aplastic anemia in the heterozygous state (PMID: 17478638). However, further studies are needed to establish the association between heterozygous pathogenic variants in SBDS and aplastic anemia. Clinical correlation is recommended. - |
Shwachman-Diamond syndrome 1 Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 02, 2023 | The heterozygous p.Ser41AlafsTer18 variant in SBDS was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 3196), in one individual with Swachman-Diamond syndrome. This individual also carried a pathogenic variant (ClinVar Variation ID: 3196), however the phase of these variants are unknown at this time. The p.Ser41AlafsTer18 variant in SBDS has been previously reported in at least 5 unrelated individuals with Swachman-Diamond syndrome (PMID: 31475115, PMID: 17539775, PMID: 24388329, PMID: 14984468) but has been identified in 0.002% (2/113580) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1175585213). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. These 5 previously reported unrelated individuals were compound heterozygotes who carried a reported pathogenic variant in unknown phase (ClinVar Variation ID: 3196, PMID: 31475115, PMID: 17539775, PMID: 24388329, PMID: 14984468), which increases the likelihood that the p.Ser41AlafsTer18 variant in SBDS is pathogenic. This variant has also been reported in ClinVar (Variation ID: 265256) and has been interpreted as pathogenic by GeneDx, Fulgent Genetics, and University of Chicago Genetic Services Laboratory. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 41 and leads to a premature termination codon 18 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SBDS gene is an established disease mechanism in autosomal recessive Swachman-Diamond syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Swachman-Diamond syndrome. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_Supporting (Richards 2015). - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Aplastic anemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 15, 2023 | - - |
Aplastic anemia;C4692625:Shwachman-Diamond syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 19, 2022 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at