rs113993994

Variant names:

• chr7-66993375-GTCTT-G
• rs113993994
• NM_016038.4:c.297_300delAAGA

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_016038.4(SBDS):​c.297_300delAAGA​(p.Glu99AspfsTer21) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000112 in 1,613,940 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 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: SBDS NM_016038.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 7.00

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-66993375-GTCTT-G is Pathogenic according to our data. Variant chr7-66993375-GTCTT-G is described in ClinVar as [Pathogenic]. Clinvar id is 21539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-66993375-GTCTT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SBDS	NM_016038.4	c.297_300delAAGA	p.Glu99AspfsTer21	frameshift_variant	Exon 3 of 5	ENST00000246868.7	NP_057122.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SBDS	ENST00000246868.7	c.297_300delAAGA	p.Glu99AspfsTer21	frameshift_variant	Exon 3 of 5	1	NM_016038.4	ENSP00000246868.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152134 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461806 Hom.: 0 AF XY: 0.00000825 AC XY: 6 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152134 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 26, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed with a second SBDS variant in two other unrelated families in published literature (PMID: 15701631); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as c.292_295delAAAG; This variant is associated with the following publications: (PMID: 15701631, 15942154) -

Shwachman-Diamond syndrome 1 Pathogenic:1 Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 07, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Glu99AspfsTer21 variant has been reported in 4 individuals with Shwachman-Diamond syndrome (PMID: 15769891, 14749921, 15942154), and has been identified in 0.001% (16/1180000) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs113993994). 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: 21539) and has been interpreted as pathogenic by multiple submitters. Of the 4 affected individuals, 2 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Glu99AspfsTer21 variant is pathogenic (Variation ID: 3196; PMID: 14749921, PMID:15942154). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 99 and leads to a premature termination codon 21 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 Shwachman-Diamond syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Shwachman-Diamond syndrome. ACMG/AMP Criteria applied: PVS1, PM3_strong, PM2_supporting (Richards 2015). -

Aplastic anemia Pathogenic:1

Jul 07, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aplastic anemia;C4692625:Shwachman-Diamond syndrome 1 Pathogenic:1

Apr 22, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SBDS-related disorder Pathogenic:1

Jan 24, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SBDS c.297_300delAAGA variant is predicted to result in a frameshift and premature protein termination (p.Glu99Aspfs*21). This variant has been reported to be causative for Shwachman-Diamond Syndrome (Shammas et al. 2005. PubMed ID: 15701631, reported as 292_295delAAAG). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. Frameshift variants in SBDS are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs113993994; hg19: chr7-66458362;