rs113993991

chr7-66994286-TA-AG

Variant summary

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

The NM_016038.4(SBDS):c.183_184delinsCT(p.Lys62Ter) variant causes a stop gained change. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S61S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SBDS NM_016038.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16 O:1
• Conservation: PhyloP100: 7.01

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 7-66994286-TA-AG is Pathogenic according to our data. Variant chr7-66994286-TA-AG is described in ClinVar as [Pathogenic]. Clinvar id is 3195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SBDS	NM_016038.4	c.183_184delinsCT	p.Lys62Ter	stop_gained	2/5	ENST00000246868.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SBDS	ENST00000246868.7	c.183_184delinsCT	p.Lys62Ter	stop_gained	2/5	1	NM_016038.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Shwachman-Diamond syndrome 1 Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	case-control	Genetics Laboratory, Department of Biology, Semnan University	Dec 30, 2020	The identified mutation changes the splicing process of SBDS gene. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 31, 2023	c.183_184delinsCT is a recurring variant known to cause Shwachman-Diamond syndrome 1 and arises from a gene-conversion event between SBDS and its pseudogene SBDSP1. It has been reported in ClinVar (Variation ID 3195). This nonsense variant results in a premature stop codon in exon 2 of 5, likely leading to nonsense-mediated decay and lack of protein production. We consider c.183_184delinsCT in SBDS to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Shwachman-Diamond syndrome (MIM#260400). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition. This variant is present in gnomAD (v3) separately as chr7:66994286T>A and chr7:66994287A>G (both 121 heterozygotes, 0 homozygotes). Based on their pattern of co-occurrence, these variants are likely found on the same haplotype in most individuals in gnomAD. (SP) 0702 - Other NMD-predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity. There are at least five NMD-predicted variants that have been classified as pathogenic or likely pathogenic (DECIPHER, ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and is one of the most common pathogenic SBDS variants (ClinVar, GeneReviews, PMID: 30413969). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_016038.2(SBDS):c.258+2T>C) in a recessive disease. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 27, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 21, 2021	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 02, 2022	PM2_supporting, PS3, PS4, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	SBDS: PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2019	Nonsense 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; This variant is associated with the following publications: (PMID: 14749921, 24388329, 25729736, 32098966, 22934832, 15860664, 22935661, 12496757, 15342903, 25844324, 24629175, 26081292, 29444436, 29892551, 28485484, 29375851, 29753700, 15942154, 16007594, 15474150, 30198570, 17920346, 30105119, 15701631, 21695142, 30894704, 32293785, 31589614) -

Aplastic anemia;C4692625:Shwachman-Diamond syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Aug 23, 2022	This variant is very well described in the literature in association with Shwachman-Diamond syndrome and is one of the most common pathogenic variants in the SBDS gene, most often found in trans with c.258+2T>C (Boocock 2003 PMID:12496757; Shammas 2005 PMID:15701631; Nelson 2018 PMID:20301722). It is present in the Genome Aggregation Database (Highest reported MAF: 0.05% [9/19936]; https://gnomad.broadinstitute.org/variant/7-66459273-T-A?dataset=gnomad_r2_1); please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. It is present in ClinVar, with several laboratories classifying it was pathogenic (Variation ID:3195). This variant creates a premature stop at this codon which results in an abnormal protein, and has been experimentally confirmed to result in a loss of protein function due to impaired cytoplasmic localization in vitro (Shammas 2005 PMID:15701631; Orelio 2011 PMID:21695142). Loss of function is a known mechanism of disease for this gene (Nelson 2018 PMID:20301722). Importantly, this variant has been documented to be present in a highly homologous pseudogene of SBDS, and is often introduced into the functional SBDS gene via a gene conversion event; gene conversion events involving SBDS and its pseudogene (SBDSP1) are a well-documented cause of Shwachman-Diamond syndrome in some individuals (Boocock 2003 PMID:12496757; Nelson 2018 PMID:20301722). In summary, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 09, 2021	- -

Aplastic anemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 30, 2023

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2023

The c.183_184delTAinsCT (p.K62*) alteration, located in exon 2 (coding exon 2) of the SBDS gene, consists of an in-frame deletion of TA and insertion of CT at nucleotide positions 183 to 184. This changes the amino acid at position 62 from a lysine (K) to a stop codon. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation was reported in 82 of 250 disease alleles in a cohort of individuals with Shwachman-Diamond syndrome. In eight of the families studied, this mutation was found as part of a complex allele, c.[183_184delTAinsCT;258+2T>C], in trans with an isolated copy of c.258+2T>C (Boocock, 2003). In another study, this alteration was described compound heterozygous with c.258+2T>C in five individuals who presented with pancreatic insufficiency and failure to thrive; three of those individuals also had persistent neutropenia (Kawakami, 2005). A functional study in yeast cells found that this mutation resulted in complete loss of function (Shammas, 2005). Based on the available evidence, this alteration is classified as pathogenic. -

SBDS-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 25, 2024

The SBDS c.183_184delinsCT variant is predicted to result in premature protein termination (p.Lys62*). This variant has been reported in many individuals with Shwachman-Diamond syndrome when found with another pathogenic variant (see for example Boocock et al. 2003. PubMed ID: 12496757; Myers et al. 2014. PubMed ID: 24388329). This variant is documented separately as c.183T>C and c.184A>T in gnomAD, therefore the reported gnomAD frequency for this variant may not be accurate. Loss-of-function variants in SBDS are expected to be pathogenic. This variant is interpreted as pathogenic. -

Shwachman syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 16, 2024

The p.Lys62X variant in SBDS is the most common pathogenic variant identified in individuals with Shwachman-Diamond syndrome (Boocock 2003 PMID: 12496757). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 3195) and has been identified in 0.1% (69/59956) of Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0); however, this allele frequency may not be accurate due to the presence of a pseudogene (SBDSP). Note that this variant was documented separately as chr7:66994286T>A and chr7:66994287A>G in gnomAD. This variant usually occurs as the result of a gene conversion event and results in the introduction of a premature termination codon at position 62. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the SBDS gene is an established disease mechanism in 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_Very Strong. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs113993991; hg19: chr7-66459273;