X-21967298-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_004595.5(SMS):c.152A>G(p.Tyr51Cys) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 21)
• Consequence: SMS NM_004595.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.96

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749
• PP5: Variant X-21967298-A-G is Pathogenic according to our data. Variant chrX-21967298-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1210218.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMS	NM_004595.5	c.152A>G	p.Tyr51Cys	missense_variant	2/11	ENST00000404933.7
SMS	NM_001258423.2	c.152A>G	p.Tyr51Cys	missense_variant	2/9
SMS	XM_005274582.3	c.50A>G	p.Tyr17Cys	missense_variant	2/11
SMS	XM_011545568.3	c.50A>G	p.Tyr17Cys	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMS	ENST00000404933.7	c.152A>G	p.Tyr51Cys	missense_variant	2/11	1	NM_004595.5	P1
SMS	ENST00000457085.2	c.497A>G	p.Tyr166Cys	missense_variant	2/6	5
SMS	ENST00000379404.5	c.152A>G	p.Tyr51Cys	missense_variant	2/9	3
SMS	ENST00000478094.1	n.199A>G		non_coding_transcript_exon_variant	2/5	4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 21

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Syndromic X-linked intellectual disability Snyder type Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Randwick Genomics Laboratory, Prince of Wales Hospital Sydney, Australia, New South Wales Health Pathology

-

PM2, PS4_moderate, PP4_moderate -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 12, 2020

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.18	T;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Uncertain	0.0089	D
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.8	D;N
REVEL	Uncertain	0.60
Sift	Uncertain	0.0030	D;T
Sift4G	Uncertain	0.012	D;T
Polyphen		0.99	D;B
Vest4		0.82
MutPred		0.45		Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);
MVP		0.98
MPC		1.2
ClinPred		0.96	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-21985416;