rs121434610
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_004595.5(SMS):c.166G>A(p.Gly56Ser) variant causes a missense change. 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 Pathogenic (★★).
Frequency
Genomes: not found (cov: 21)
Consequence
SMS
NM_004595.5 missense
NM_004595.5 missense
Scores
4
4
9
Clinical Significance
Conservation
PhyloP100: 6.92
Genes affected
SMS (HGNC:11123): (spermine synthase) This gene encodes a protein belonging to the spermidine/spermin synthase family and catalyzes the production of spermine from spermidine. Pseudogenes of this gene are located on chromosomes 1, 5, 6 and X. Mutations in this gene cause an X-linked intellectual disability called Snyder-Robinson Syndrome (SRS). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.929
PP5
?
Variant X-21967312-G-A is Pathogenic according to our data. Variant chrX-21967312-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-21967312-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMS | NM_004595.5 | c.166G>A | p.Gly56Ser | missense_variant | 2/11 | ENST00000404933.7 | |
SMS | NM_001258423.2 | c.166G>A | p.Gly56Ser | missense_variant | 2/9 | ||
SMS | XM_005274582.3 | c.64G>A | p.Gly22Ser | missense_variant | 2/11 | ||
SMS | XM_011545568.3 | c.64G>A | p.Gly22Ser | missense_variant | 2/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMS | ENST00000404933.7 | c.166G>A | p.Gly56Ser | missense_variant | 2/11 | 1 | NM_004595.5 | P1 | |
SMS | ENST00000457085.2 | c.511G>A | p.Gly171Ser | missense_variant | 2/6 | 5 | |||
SMS | ENST00000379404.5 | c.166G>A | p.Gly56Ser | missense_variant | 2/9 | 3 | |||
SMS | ENST00000478094.1 | n.213G>A | non_coding_transcript_exon_variant | 2/5 | 4 |
Frequencies
GnomAD3 genomes ? Cov.: 21
GnomAD3 genomes
?
Cov.:
21
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome ? Cov.: 21
GnomAD4 genome
?
Cov.:
21
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Syndromic X-linked intellectual disability Snyder type Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2008 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 15, 2013 | ​SMS c.166G>A (p.G56S):The c.166G>A (p.G56S) alteration is located in exon 2 of the SMS gene. This alteration results from a G to A substitution at nucleotide position 166. The glycine (G) at codon 56 is replaced by serine (S).The missense change is not observed in healthy cohorts:Based on data from the NHLBI Exome Sequencing Project (ESP), the SMS c.166G>A (p.G56S) alteration was not observed among 6,503 individuals tested (0.0%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project. The alteration is currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP) as rs121434610.The altered amino acid is conserved throughout evolution:The p.G56 amino acid is conserved throughout vertebrates.in silico prediction is conflicting:The p.G56S alteration is predicted to be benign by Polyphen and by SIFT in silico analyses. However, structure-based computational analysis predicts that the p.G56S alteration reduces the affinity of monomers to form a dimer and leads to structural reorganization and destabilization of the SMS monomer (Zhang et al, 2010). Further, computational analysis involving binding free energycalculations predict a decrease in dimer affinity with any substitution at amino acid G56 (Zhang et al., 2011).The amino acid is located in a functionally important protein domain:The p.G56 amino acid is located in the N-terminal region of the SMS protein, which is essential for proper dimerisation and ability to catalyze spermine from spermidine (Ikeguchi et al., 2006; de Alencastro et al., 2008).The amino acid change has been observed in affected individuals:The p.G56S alteration is reported in the HGMD database (CM083784). The alteration co-segregated in a large Brazilian kindred with Snyder-Robinson syndrome with marked clinical variability and was not identified among 724 control chromosomes (de Alencastro et al., 2008). Female carriers manifested skewed X-inactivation, consistent with the original Snyder-Robinson syndrome family(de Alencastro et al., 2008).Functional analysis reveals a damaging effect of the amino acid alteration:Analysis of immortalizedlymphoblastoid cell lines (LCL) in patients with the p.G56S alterationrevealeda marked decrease in enzyme activity(de Alencastro et al., 2008). Further, in vitro analysis involving site-directed mutagenesis and western blot analysis demonstrated that the G56S alteration resulted in a reduction in dimers formation as compared to wild type (Zhang et al., 2011).Based on the available evidence, the SMS c.166G>A (p.G56S) alteration is classified as a pathogenic mutation.de Alencastro, et al. (2008) J Med Genet 45:539-543.Zhang Z, et al. (2010) Hum Mutat 31(9):1043–1049.Zhang Z, et al. (2011) PLoS One 6(5):e20373. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 03, 2022 | Published functional studies demonstrate a damaging effect as in vitro studies reveal the G56 site is sensitive to charge residue replacement with the G56S variant predicted to lower dimer affinity (Zhang et al., 2011) In addition, lymphoblastoid cell lines from affected males had no detectable spermine synthase enzyme activity (de Alencastro et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20556796, 23408511, 18550699, 26761001, 26350204, 30237987, 23805436, 31580924, 21647366) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
A;A;A
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;P
Vest4
MutPred
Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at