X-21967257-G-T

Position:

• chrX-21967257-G-T

Variant summary

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

The ENST00000404933.7(SMS):​c.111G>T​(p.Glu37Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,837 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: SMS ENST00000404933.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.37

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, 0.796

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMS	NM_004595.5	c.111G>T	p.Glu37Asp	missense_variant	2/11	ENST00000404933.7	NP_004586.2
SMS	NM_001258423.2	c.111G>T	p.Glu37Asp	missense_variant	2/9		NP_001245352.1
SMS	XM_005274582.3	c.9G>T	p.Glu3Asp	missense_variant	2/11		XP_005274639.1
SMS	XM_011545568.3	c.9G>T	p.Glu3Asp	missense_variant	2/11		XP_011543870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMS	ENST00000404933.7	c.111G>T	p.Glu37Asp	missense_variant	2/11	1	NM_004595.5	ENSP00000385746	P1
SMS	ENST00000457085.2	c.456G>T	p.Glu152Asp	missense_variant	2/6	5		ENSP00000407366
SMS	ENST00000379404.5	c.111G>T	p.Glu37Asp	missense_variant	2/9	3		ENSP00000368714
SMS	ENST00000478094.1	n.158G>T		non_coding_transcript_exon_variant	2/5	4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096837 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 362247

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: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

SMS-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2023

The SMS c.111G>T variant is predicted to result in the amino acid substitution p.Glu37Asp. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T;.
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.73	N;N
REVEL	Uncertain	0.48
Sift	Benign	0.33	T;D
Sift4G	Benign	0.39	T;D
Polyphen		0.90	P;D
Vest4		0.50
MutPred		0.62		Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);
MVP		0.94
MPC		0.87
ClinPred		0.77	D
GERP RS		2.0
Varity_R		0.68
gMVP		0.52

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: rs762162684; hg19: chrX-21985375; COSMIC: COSV101048283;