X-21967312-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• 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]

ACMG classification

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

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Syndromic X-linked intellectual disability Snyder type Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2008	- -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.061	T;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	T;T
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.63
Sift	Benign	0.096	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.42	B;P
Vest4		0.85
MutPred		0.73		Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);
MVP		1.0
MPC		1.8
ClinPred		0.92	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121434610; hg19: chrX-21985430;