rs267607076

Positions:

• chrX-21977126-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The ENST00000404933.7(SMS):​c.395T>G​(p.Val132Gly) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: SMS ENST00000404933.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.64

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.

• PM1: In a domain PABS (size 240) in uniprot entity SPSY_HUMAN there are 19 pathogenic changes around while only 3 benign (86%) in ENST00000404933.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904
• PP5: Variant X-21977126-T-G is Pathogenic according to our data. Variant chrX-21977126-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 11625.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMS	NM_004595.5	c.395T>G	p.Val132Gly	missense_variant	5/11	ENST00000404933.7	NP_004586.2
SMS	NM_001258423.2	c.236T>G	p.Val79Gly	missense_variant	3/9		NP_001245352.1
SMS	XM_005274582.3	c.293T>G	p.Val98Gly	missense_variant	5/11		XP_005274639.1
SMS	XM_011545568.3	c.293T>G	p.Val98Gly	missense_variant	5/11		XP_011543870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMS	ENST00000404933.7	c.395T>G	p.Val132Gly	missense_variant	5/11	1	NM_004595.5	ENSP00000385746	P1
SMS	ENST00000457085.2	c.740T>G	p.Val247Gly	missense_variant	5/6	5		ENSP00000407366
SMS	ENST00000379404.5	c.236T>G	p.Val79Gly	missense_variant	3/9	3		ENSP00000368714
SMS	ENST00000478094.1	n.348T>G		non_coding_transcript_exon_variant	4/5	4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Syndromic X-linked intellectual disability Snyder type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;T
Polyphen		1.0	D;D
Vest4		0.41
MutPred		0.85		Loss of stability (P = 0.0236);.;
MVP		0.99
MPC		2.3
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs267607076; hg19: chrX-21995244;