rs113993990

Positions:

• chr7-66995297-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: 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	Protein	UniProt
SBDS	NM_016038.4	c.120del	p.Ser41AlafsTer18	frameshift_variant	1/5	ENST00000246868.7	NP_057122.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SBDS	ENST00000246868.7	c.120del	p.Ser41AlafsTer18	frameshift_variant	1/5	1	NM_016038.4	ENSP00000246868	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251248 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000411 AC: 6 AN: 1461448 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727024

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74370

Gnomad4 AFR AF: 0.00

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

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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:1 Other: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

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: rs113993990; hg19: chr7-66460284;