7-66988472-G-A

Variant names:

• chr7-66988472-G-A
• rs113993998
• NM_016038.4:c.652C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_016038.4(SBDS):​c.652C>T​(p.Arg218*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,572 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SBDS NM_016038.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 0.0240

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.134 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PP5: Variant 7-66988472-G-A is Pathogenic according to our data. Variant chr7-66988472-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-66988472-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SBDS	NM_016038.4	c.652C>T	p.Arg218*	stop_gained	Exon 5 of 5	ENST00000246868.7	NP_057122.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SBDS	ENST00000246868.7	c.652C>T	p.Arg218*	stop_gained	Exon 5 of 5	1	NM_016038.4	ENSP00000246868.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251270 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135840

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: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461572 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727100

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000594 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aplastic anemia Pathogenic:2

Sep 24, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with a termination signal at codon 218 of the SBDS protein (p.Arg218Ter). Null variant (nonsense), in gene SBDS, for which loss-of-function is a known mechanism of disease (associated with Shwachman-Diamond syndrome 1 and Aplastic anemia. ClinVar classifies this variant as Pathogenic, rated 0 stars, no assertion criteria provided, with 1 submission, 1 publication (15284109). In-silico prediction models show pathogenic computational verdict based on 4 pathogenic predictions from BayesDel_addAF, DANN, FATHMM-MKL and MutationTaster vs 1 benign prediction from EIGEN. Therefore, this variant is classified as likely pathogenic. -

Shwachman-Diamond syndrome 1 Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 06, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Arg218Ter variant in SBDS has been reported in two individuals with Shwachman-Diamond syndrome (PMID: 15284109, PMID: 15776428), and has been identified in 0.001% (1/74986) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs113993998). 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: 21545) and has been interpreted as likely pathogenic/pathogenic by GeneDx, KCCC/NGS Laboratory (Kuwait Cancer Control Center) and Baylor Genetics. Both of the affected individuals were compound heterozygotes that carried a reported pathogenic variant, one of which in trans, which increases the likelihood that the p.Arg218Ter variant is pathogenic (ClinVar Variation ID: 3196; PMID: 15284109, PMID: 15776428). This nonsense variant leads to a premature termination codon at position 218. This alteration occurs within the last exon, and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the SBDS gene is an established disease mechanism in autosomal recessive Shwachman-Diamond syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Shwachman-Diamond syndrome. ACMG/AMP Criteria applied: PVS1_strong, PM3, PM2_supporting (Richards 2015). -

not provided Pathogenic:1

Aug 11, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation as the last 33 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 21695142, 29625052, 15776428, 15284109) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Benign	0.16
Eigen_PC	Benign	-0.047
FATHMM_MKL	Benign	0.68	D
Vest4		0.93
GERP RS		-1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs113993998; hg19: chr7-66453459; COSMIC: COSV55887178; COSMIC: COSV55887178;