rs120074160
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_016038.4(SBDS):c.184A>T(p.Lys62*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000527 in 1,613,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_016038.4 stop_gained
Scores
Clinical Significance
Conservation
Publications
- Shwachman-Diamond syndromeInheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
- Shwachman-Diamond syndrome 1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_016038.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SBDS | NM_016038.4 | MANE Select | c.184A>T | p.Lys62* | stop_gained | Exon 2 of 5 | NP_057122.2 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SBDS | ENST00000246868.7 | TSL:1 MANE Select | c.184A>T | p.Lys62* | stop_gained | Exon 2 of 5 | ENSP00000246868.2 | ||
| SBDS | ENST00000697897.1 | c.184A>T | p.Lys62* | stop_gained | Exon 3 of 6 | ENSP00000513469.1 | |||
| SBDS | ENST00000697863.1 | c.127A>T | p.Lys43* | stop_gained | Exon 3 of 6 | ENSP00000513462.1 |
Frequencies
GnomAD3 genomes 0.00103 AC: 157AN: 152172Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000167 AC: 42AN: 251300 AF XY: 0.000147 show subpopulations
GnomAD4 exome AF: 0.000474 AC: 692AN: 1460940Hom.: 0 Cov.: 32 AF XY: 0.000490 AC XY: 356AN XY: 726790 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
Age Distribution
GnomAD4 genome 0.00104 AC: 158AN: 152288Hom.: 0 Cov.: 32 AF XY: 0.00110 AC XY: 82AN XY: 74458 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Shwachman-Diamond syndrome 1 Pathogenic:8
It is observed in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org) dataset (total allele frequency: 0.388% NA). Predicted Consequence/Location: Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21695142). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000003196 /PMID: 12496757 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
The stop gained p.K62* in SBDS (NM_016038.4) has been previously reported as c.183_184delinsCT. It is known to occur both in cis with 258+2T>C as a complex allele due to gene conversion as well as in trans with c.258+2T>C. The variant is one amongst the three common pathogenic variants, all arising due to gene conversion with the highly homologous pseudogene SBDSP (Nelson AS et al,2018). This variant is predicted to cause loss of normal protein function through protein truncation. Functional studies demonstrate loss of function (Orelio et al,2011). The variant has been submitted to ClinVar as Pathogenic. For these reasons, this variant has been classified as Pathogenic.
The p.Lys62Ter variant in SBDS has been reported in >10 individuals with Shwachman-Diamond syndrome (PMID: 12496757, 15284109, 15769891, 24388329), and has been identified in 0.1% (69/59956) of Admixed chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs120074160). Although this variant has been seen in the general population in the heterozygous state, its frequency is not high enough to rule out a pathogenic role. The presence of a known pseudogene, SBDSP1, can also impact the reliability of allele frequencies. This variant has also been reported in ClinVar (Variation ID: 449095) and has been interpreted as Pathogenic or Likely pathogenic by multiple submitters. Of the affected individuals, many were compound heterozygotes that carried a reported pathogenic variant in trans (Variation ID: 3196; PMID: 12496757, 15284109, 15769891, 24388329). In vitro functional studies provide evidence that the p.Lys62Ter variant may impact protein function (PMID: 15284109, 15860664). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 62, which is 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: PM3_very-strong, PVS1, PS3 (Richards 2015).
The SBDS c.184A>T variant is classified as PATHOGENIC (PVS1, PS3, PS4, PM3) The SBDS c.184A>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 62 (PVS1). This variant has been reported many times in conjunction with a second pathogenic variant (NM_016038.4(SBDS):c.258+2T>C) in association with Shwachman-Diamond syndrome (PS4), as is the case with this patient (PM3). Functional studies have shown this variant affects the protein's cellular localisation and motility (PMID:21695142) (PS3). The variant has been reported in dbSNP (rs120074160) and in the HGMD database: CP035464. It has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 449095).
Variant summary: SBDS c.184A>T (p.Lys62X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00017 in 251300 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SBDS causing Shwachman-Diamond Syndrome 1, allowing no conclusion about variant significance. c.184A>T has been reported in the literature in multiple individuals affected with Shwachman-Diamond Syndrome 1 (examples:Furutani_2022, Walne_2021, Mitri_2021). These data indicate that the variant is very likely to be associated with disease. This variant is also reported as c.183_184delTAinsCT. The following publications have been ascertained in the context of this evaluation (PMID: 34758064, 33871916, 34625797). ClinVar contains an entry for this variant (Variation ID: 449095). Based on the evidence outlined above, the variant was classified as pathogenic.
not provided Pathogenic:8
The K62X variant in the SBDS gene has been reported previously in an individual with Shwachman-Diamond syndrome who also harbored the c.258+2 T>C variant on the other SBDS allele (Pronicka et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Functional studies demonstrate that the K62X variant results in abnormally low cytoplasmic protein levels and loss of protein function (Orelio et al., 2011; Shammas et al., 2005). The K62X variant is not observed in large population cohorts (Lek et al., 2016). Historically this variant as been reported as c.183_184delTAinsCT. This event is derived from a recombination event with a known psuedogene carrying this variant.
DNA sequence analysis of the SBDS gene demonstrated a two base pair deletion and two base pair insertion in exon 2, c.183_184delinsCT. This pathogenic sequence change results in the formation of a premature stop codon, p.Lys62*. This pathogenic 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 pathogenic sequence change has previously been described in the compound heterozygous state with a second pathogenic variant in SBDS in multiple individuals with SDS (PMID: 12496757, 15942154).
Aplastic anemia;C4692625:Shwachman-Diamond syndrome 1 Pathogenic:2
Intellectual disability Pathogenic:2
The variant chr7-66459273-T-A, SBDS(NM_016038.4):c.184A>T,p.(Lys62*) was identified in an individual with NDD. Inheritance was paternal (heterozygous). The variant was reviewed according to current ACMG recommendations and classified as Pathogenic (criteria: PSV1_VeryStrong, PM2_Supporting, PS3_Moderate, PM3_Moderate). This variant was identified in a compound heterozygous state with the variant NM_016038.4(SBDS):c.258+2T>C (Variation ID: 3196).
Inborn genetic diseases Pathogenic:1
The c.184A>T (p.K62*) alteration, located in exon 2 (coding exon 2) of the SBDS gene, consists of a A to T substitution at nucleotide position 184. This changes the amino acid from a lysine (K) to a stop codon at amino acid position 62. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.026% (73/282686) total alleles studied. The highest observed frequency was 0.045% (9/19936) of East Asian alleles. This variant has been confirmed in trans with a SBDS pathogenic variant in an individual with clinical features of Shwachman-Diamond syndrome (Tan, 2021). Based on the available evidence, this alteration is classified as pathogenic.
Splenomegaly;C0349588:Short stature;C0423224:Deeply set eye;C1290511:Agenesis of permanent teeth;C4551563:Microcephaly Pathogenic:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at