X-21967282-G-A

Position:

• chrX-21967282-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004595.5(SMS):​c.136G>A​(p.Gly46Ser) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: SMS NM_004595.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.76

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMS	NM_004595.5	c.136G>A	p.Gly46Ser	missense_variant	2/11	ENST00000404933.7	NP_004586.2
SMS	NM_001258423.2	c.136G>A	p.Gly46Ser	missense_variant	2/9		NP_001245352.1
SMS	XM_005274582.3	c.34G>A	p.Gly12Ser	missense_variant	2/11		XP_005274639.1
SMS	XM_011545568.3	c.34G>A	p.Gly12Ser	missense_variant	2/11		XP_011543870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMS	ENST00000404933.7	c.136G>A	p.Gly46Ser	missense_variant	2/11	1	NM_004595.5	ENSP00000385746	P1
SMS	ENST00000457085.2	c.481G>A	p.Gly161Ser	missense_variant	2/6	5		ENSP00000407366
SMS	ENST00000379404.5	c.136G>A	p.Gly46Ser	missense_variant	2/9	3		ENSP00000368714
SMS	ENST00000478094.1	n.183G>A		non_coding_transcript_exon_variant	2/5	4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 17, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter 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	0.19
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.065	T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.0	N;N
REVEL	Pathogenic	0.66
Sift	Benign	0.14	T;D
Sift4G	Benign	0.35	T;T
Polyphen		0.20	B;P
Vest4		0.88
MutPred		0.55		Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);
MVP		1.0
MPC		1.4
ClinPred		0.92	D
GERP RS		5.2
Varity_R		0.69
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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-21985400;