chrX-21940864-G-C

Position:

• chrX-21940864-G-C

Variant summary

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

The NM_004595.5(SMS):​c.40G>C​(p.Gly14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000202 in 989,157 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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 (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000020 (0 hom. 0 hem.)
• Consequence: SMS NM_004595.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30

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=0.27681187).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMS	NM_004595.5	c.40G>C	p.Gly14Arg	missense_variant	1/11	ENST00000404933.7	NP_004586.2
SMS	NM_001258423.2	c.40G>C	p.Gly14Arg	missense_variant	1/9		NP_001245352.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMS	ENST00000404933.7	c.40G>C	p.Gly14Arg	missense_variant	1/11	1	NM_004595.5	ENSP00000385746.2
SMS	ENST00000379404.5	c.40G>C	p.Gly14Arg	missense_variant	1/9	3		ENSP00000368714.1
SMS	ENST00000478094.1	n.87G>C		non_coding_transcript_exon_variant	1/5	4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000202 AC: 2 AN: 989157 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 315059

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: 0.00000126

Gnomad4 OTH exome AF: 0.0000242

GnomAD4 genome Cov.: 22

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

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

SMS: PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.030	T;.
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.26	T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.2	L;L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.29	N;N
REVEL	Benign	0.11
Sift	Benign	0.16	T;T
Sift4G	Benign	0.61	T;T
Polyphen		0.14	B;B
Vest4		0.28
MutPred		0.52		Gain of MoRF binding (P = 0.0166);Gain of MoRF binding (P = 0.0166);
MVP		0.54
MPC		1.1
ClinPred		0.047	T
GERP RS		0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.39

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: rs1224045759; hg19: chrX-21958982;