X-21940837-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004595.5(SMS):c.13C>G(p.Arg5Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: SMS NM_004595.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0280

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2666197).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMS	NM_004595.5	c.13C>G	p.Arg5Gly	missense_variant	1/11	ENST00000404933.7
SMS	NM_001258423.2	c.13C>G	p.Arg5Gly	missense_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMS	ENST00000404933.7	c.13C>G	p.Arg5Gly	missense_variant	1/11	1	NM_004595.5	P1
SMS	ENST00000379404.5	c.13C>G	p.Arg5Gly	missense_variant	1/9	3
SMS	ENST00000478094.1	n.60C>G		non_coding_transcript_exon_variant	1/5	4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Syndromic X-linked intellectual disability Snyder type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

May 03, 2020

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	22
Dann	Benign	0.97
DEOGEN2	Benign	0.099	T;.
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.45	T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.18
Sift	Benign	0.16	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.41	B;B
Vest4		0.11
MutPred		0.33		Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);
MVP		0.63
MPC		1.1
ClinPred		0.40	T
GERP RS		1.5
Varity_R		0.42
gMVP		0.76

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: rs1921698887; hg19: chrX-21958955;