X-21940849-C-G

Variant names:

• chrX-21940849-C-G
• NM_004595.5:c.25C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004595.5(SMS):​c.25C>G​(p.Leu9Val) 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 benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: SMS NM_004595.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.245

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31513005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMS	NM_004595.5	c.25C>G	p.Leu9Val	missense_variant	Exon 1 of 11	ENST00000404933.7	NP_004586.2
SMS	NM_001258423.2	c.25C>G	p.Leu9Val	missense_variant	Exon 1 of 9		NP_001245352.1
SMS	XM_011545568.3	c.-572C>G		upstream_gene_variant			XP_011543870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMS	ENST00000404933.7	c.25C>G	p.Leu9Val	missense_variant	Exon 1 of 11	1	NM_004595.5	ENSP00000385746.2
SMS	ENST00000379404.5	c.25C>G	p.Leu9Val	missense_variant	Exon 1 of 9	3		ENSP00000368714.1
SMS	ENST00000478094.1	n.72C>G		non_coding_transcript_exon_variant	Exon 1 of 5	4
SMS	ENST00000457085.2	c.-125C>G		upstream_gene_variant		5		ENSP00000407366.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 20, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.055	T;.
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.71	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.15
Sift	Uncertain	0.023	D;D
Sift4G	Uncertain	0.052	T;T
Polyphen		0.36	B;B
Vest4		0.21
MutPred		0.67		Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.74
MPC		0.91
ClinPred		0.24	T
GERP RS		0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-21958967;