rs397515553

chrX-21992634-A-CchrX-21992634-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_004595.5(SMS):c.983A>C(p.Tyr328Ser) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y328C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: SMS NM_004595.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.42

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 8 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-21992634-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 88767.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMS	NM_004595.5	c.983A>C	p.Tyr328Ser	missense_variant	10/11	ENST00000404933.7
SMS	NM_001258423.2	c.824A>C	p.Tyr275Ser	missense_variant	8/9
SMS	XM_005274582.3	c.881A>C	p.Tyr294Ser	missense_variant	10/11
SMS	XM_011545568.3	c.881A>C	p.Tyr294Ser	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMS	ENST00000404933.7	c.983A>C	p.Tyr328Ser	missense_variant	10/11	1	NM_004595.5	P1
SMS	ENST00000379404.5	c.824A>C	p.Tyr275Ser	missense_variant	8/9	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.013	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-7.8	D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.014	D;T
Polyphen		1.0	D;.
Vest4		0.73
MutPred		0.62		Gain of disorder (P = 0.0017);.;
MVP		0.98
MPC		2.3
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.97
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397515553; hg19: chrX-22010752;