NM_016038.4:c.731_733delAAG
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM4_SupportingPP5_Moderate
The NM_016038.4(SBDS):c.731_733delAAG(p.Glu244del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000558 in 1,613,464 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_016038.4 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SBDS | NM_016038.4 | c.731_733delAAG | p.Glu244del | disruptive_inframe_deletion | Exon 5 of 5 | ENST00000246868.7 | NP_057122.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251138Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135790
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461284Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727002
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74342
ClinVar
Submissions by phenotype
not provided Pathogenic:1
The c.731_733delAAG variant in the SBDS gene causes an in-frame of codon Glutamic acid 244. The c.731_733delAAG variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, this variant was observed with a pathogenic variant on the opposite allele (in trans) in this patient. The c.731_733delAAG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, c.731_733delAAG is a strong candidate for a pathogenic variant. However, the possibility it may be a rare benign variant cannot be excluded. -
Shwachman-Diamond syndrome 1 Uncertain:1
The p.Glu244del variant in SBDS has been reported in one individual with Shwachman-Diamond syndrome (PMID: 28102861), and has been identified in 0.003% (2/63502) in European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs779179610). 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. The presence of a known pseudogene, SBDSP1, can impact the reliability of allele frequencies. This variant has also been reported in ClinVar (Variation ID: 503765) and has been interpreted as likely pathogenic by GeneDx. This variant is a deletion of an amino acid at position 244 and is not predicted to alter the protein reading-frame. This deletion is expected to impact the protein. In summary, the clinical significance of the p.Glu244del variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PM4_supporting (Richards 2015). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at