X-21971926-G-T

Variant names:

• chrX-21971926-G-T
• NM_004595.5:c.200G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_004595.5(SMS):​c.200G>T​(p.Gly67Val) variant causes a missense change involving the alteration of a 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 Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: SMS NM_004595.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.22

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant X-21971926-G-T is Pathogenic according to our data. Variant chrX-21971926-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2630815.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMS	NM_004595.5	c.200G>T	p.Gly67Val	missense_variant	Exon 3 of 11	ENST00000404933.7	NP_004586.2
SMS	XM_005274582.3	c.98G>T	p.Gly33Val	missense_variant	Exon 3 of 11		XP_005274639.1
SMS	XM_011545568.3	c.98G>T	p.Gly33Val	missense_variant	Exon 3 of 11		XP_011543870.1
SMS	NM_001258423.2	c.170+4610G>T		intron_variant	Intron 2 of 8		NP_001245352.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMS	ENST00000404933.7	c.200G>T	p.Gly67Val	missense_variant	Exon 3 of 11	1	NM_004595.5	ENSP00000385746.2
SMS	ENST00000457085.2	c.545G>T	p.Gly182Val	missense_variant	Exon 3 of 6	5		ENSP00000407366.2
SMS	ENST00000379404.5	c.170+4610G>T		intron_variant	Intron 2 of 8	3		ENSP00000368714.1
SMS	ENST00000478094.1	n.218-581G>T		intron_variant	Intron 2 of 4	4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

SMS-related disorder Pathogenic:1

Dec 12, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SMS c.200G>T variant is predicted to result in the amino acid substitution p.Gly67Val. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been observed in an individual with features consistent with Snyder-Robinson syndrome and abnormal targeted methylation analysis (Internal Data, PreventionGenetics). An alternate nucleotide change affecting the same amino acid (p.Gly67Glu) has been reported in an individual with Snyder-Robinson syndrome and experimental studies suggest it impacts protein function (Referred to as c.200G>A; p.G67X, Peron et al. 2013. PubMed ID: 23897707; Peng et al. 2016. PubMed ID: 26761001; https://www.ncbi.nlm.nih.gov/clinvar/variation/65677/). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.69		Gain of sheet (P = 0.0028);
MVP		0.99
MPC		2.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.46		Position offset: -29

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-21990044;