chr7-66994211-C-G
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_016038.4(SBDS):c.258+1G>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000149 in 1,613,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_016038.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SBDS | NM_016038.4 | c.258+1G>C | splice_donor_variant, intron_variant | Intron 2 of 4 | ENST00000246868.7 | NP_057122.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152132Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251448Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135902
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461730Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 727164
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152132Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74308
ClinVar
Submissions by phenotype
Shwachman-Diamond syndrome 1 Pathogenic:1Other:1
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The c.258+1G>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.258+1G>C variant has been reported in three studies and is found in a total of four patients with Shwachmann-Diamond syndrome in a compound heterozygous state (Boocock et al. 2003; Woloszynek et al. 2004; Hassan et al. 2009). The variant was absent from 148 controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. The c.258+1G>C splice donor variant interrupts the intron 2 invariant splice donor site which results in the use of a cryptic splice donor site at cDNA position 251-252. The abnormally spliced mRNA results in a frameshift at amino acid position 84 with subsequent premature truncation of the protein after an additional three amino acids (Boocock et al. 2003; Woloszynek et al. 2004). A different variant at the c.258+2 position in the same intron 2 invariant splice donor site results in an identical frameshift and is one of the most common known pathogenic variants in the SBDS gene. Based on the collective evidence, the c.258+1G>C variant is classified as pathogenic for Shwachmann-Diamond syndrome. -
Aplastic anemia Pathogenic:1
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Inborn genetic diseases Pathogenic:1
The c.258+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 2 of the SBDS gene. This mutation was first reported in two alleles from 158 unrelated families with at least one individual with Shwachman-Diamond syndrome (SDS) (Boocock GR et al. Nat. Genet., 2003 Jan;33:97-101). In another study, this mutation was identified in conjunction with the common c.258+2T>C pathogenic mutation in an individual suspected to have SDS; however, the phase of the alterations was not provided (Woloszynek JR et al. Blood, 2004 Dec;104:3588-90). In our internal cohort, this mutation was confirmed in trans with a complex allele including c.258+2T>C in an individual with pancytopenia, pancreatic insufficiency, and skeletal abnormalities. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -
Aplastic anemia;C4692625:Shwachman-Diamond syndrome 1 Pathogenic:1
SBDS NM_016038.3 exon 2 c.258+1G>C: This variant has been reported in the literature in at least 2 individuals (zygosity unclear) with Shwachman-Diamond Syndrome (Boocock 2003 PMID:12496757, Woloszynek 2004 PMID:15284109). This variant is present in 3/126700 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs113993992). This variant is present in ClinVar (Variation ID:21538). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2) which is predicted to result in an absent or abnormal protein. Loss of function has been reported as a disease mechanism for this gene and disease (Woloszynek 2004 PMID:15284109). In summary, this variant is classified as pathogenic . -
not provided Pathogenic:1
Canonical splice site variant in intron 2 of the SBDS gene, for which loss-of-function is a known mechanism of disease (Nelson & Meyers, 2018); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28971907, 23351992, 20301722, 12496757, 17916435, 24898207, 15284109) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at