rs397515551

chrX-21977174-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_004595.5(SMS):c.443A>G(p.Gln148Arg) 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 NM_004595.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 8.90

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 9 ACMG points.

• PM1: In a domain PABS (size 240) in uniprot entity SPSY_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_004595.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant X-21977174-A-G is Pathogenic according to our data. Variant chrX-21977174-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 65679.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMS	NM_004595.5	c.443A>G	p.Gln148Arg	missense_variant	5/11	ENST00000404933.7
SMS	NM_001258423.2	c.284A>G	p.Gln95Arg	missense_variant	3/9
SMS	XM_005274582.3	c.341A>G	p.Gln114Arg	missense_variant	5/11
SMS	XM_011545568.3	c.341A>G	p.Gln114Arg	missense_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMS	ENST00000404933.7	c.443A>G	p.Gln148Arg	missense_variant	5/11	1	NM_004595.5	P1
SMS	ENST00000457085.2	c.788A>G	p.Gln263Arg	missense_variant	5/6	5
SMS	ENST00000379404.5	c.284A>G	p.Gln95Arg	missense_variant	3/9	3
SMS	ENST00000478094.1	n.396A>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 Other:1

Revision: no assertion criteria provided

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	Undiagnosed Diseases Program Translational Research Laboratory, National Institutes of Health	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.3	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.90		Gain of ubiquitination at K151 (P = 0.1222);.;
MVP		1.0
MPC		1.9
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.96
gMVP		1.0

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: rs397515551; hg19: chrX-21995292; COSMIC: COSV65114197;