rs1441016865

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_016038.4(SBDS):​c.102C>G​(p.Asn34Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N34I) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

SBDS
NM_016038.4 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.34

Publications

0 publications found
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]
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_016038.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-66995317-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2678601.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.909

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SBDSNM_016038.4 linkc.102C>G p.Asn34Lys missense_variant Exon 1 of 5 ENST00000246868.7 NP_057122.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SBDSENST00000246868.7 linkc.102C>G p.Asn34Lys missense_variant Exon 1 of 5 1 NM_016038.4 ENSP00000246868.2 Q9Y3A5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251432
AF XY:
0.00
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Dec 09, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.N34K variant (also known as c.102C>G), located in coding exon 1 of the SBDS gene, results from a C to G substitution at nucleotide position 102. The asparagine at codon 34 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.070
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.92
D;T
Eigen
Pathogenic
0.74
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
1.0
D;D
M_CAP
Pathogenic
0.68
D
MetaRNN
Pathogenic
0.91
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.7
H;.
PhyloP100
3.3
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-5.5
D;.
REVEL
Pathogenic
0.83
Sift
Uncertain
0.0010
D;.
Sift4G
Uncertain
0.0020
D;D
Polyphen
1.0
D;.
Vest4
0.73
MutPred
0.74
Gain of catalytic residue at N34 (P = 0.008);Gain of catalytic residue at N34 (P = 0.008);
MVP
0.99
MPC
1.4
ClinPred
1.0
D
GERP RS
4.3
PromoterAI
-0.030
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.91
gMVP
0.79
Mutation Taster
=10/90
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs1441016865; hg19: chr7-66460303; API