X-21992634-A-G

Position:

• chrX-21992634-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1 PP3_Moderate PP5 BS2

The NM_004595.5(SMS):​c.983A>G​(p.Tyr328Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000183 in 1,092,446 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. 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)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
• Consequence: SMS NM_004595.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• 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 Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a domain PABS (size 240) in uniprot entity SPSY_HUMAN there are 15 pathogenic changes around while only 2 benign (88%) in NM_004595.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924
• PP5: Variant X-21992634-A-G is Pathogenic according to our data. 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.
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMS	NM_004595.5	c.983A>G	p.Tyr328Cys	missense_variant	10/11	ENST00000404933.7
SMS	NM_001258423.2	c.824A>G	p.Tyr275Cys	missense_variant	8/9
SMS	XM_005274582.3	c.881A>G	p.Tyr294Cys	missense_variant	10/11
SMS	XM_011545568.3	c.881A>G	p.Tyr294Cys	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMS	ENST00000404933.7	c.983A>G	p.Tyr328Cys	missense_variant	10/11	1	NM_004595.5	P1
SMS	ENST00000379404.5	c.824A>G	p.Tyr275Cys	missense_variant	8/9	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1092446 Hom.: 0 Cov.: 27 AF XY: 0.00000557 AC XY: 2 AN XY: 358948

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

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

Sep 15, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.9	D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.029	D;D
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.58		Gain of catalytic residue at E330 (P = 0.2379);.;
MVP		0.98
MPC		1.9
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.94
gMVP		0.97

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; COSMIC: COSV65115514;