rs113993990

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_016038.4(SBDS):c.120delG(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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 0.597

Variant links:

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]

SBDS links:

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]

TYW1 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
SBDS	NM_016038.4 link	c.120delG	p.Ser41AlafsTer18	frameshift_variant	Exon 1 of 5	ENST00000246868.7	NP_057122.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SBDS	ENST00000246868.7 link	c.120delG	p.Ser41AlafsTer18	frameshift_variant	Exon 1 of 5	1	NM_016038.4	ENSP00000246868.2		Q9Y3A5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

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:

AN:

251248

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135864

show subpopulations

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:

AN:

1461448

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727024

show subpopulations

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:

AN:

152204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

show subpopulations

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: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‚Äôs 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

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over