X-21940733-A-G

Position:

• chrX-21940733-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004595.5(SMS):​c.-92A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 741,930 control chromosomes in the GnomAD database, including 20,950 homozygotes. There are 53,753 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (5940 hom., 10668 hem., cov: 21)
  • Exomes 𝑓: 0.25 (15010 hom. 43085 hem.)
• Consequence: SMS NM_004595.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.176

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant X-21940733-A-G is Benign according to our data. Variant chrX-21940733-A-G is described in ClinVar as [Benign]. Clinvar id is 1251427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMS	NM_004595.5	c.-92A>G		5_prime_UTR_variant	1/11	ENST00000404933.7
SMS	NM_001258423.2	c.-92A>G		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMS	ENST00000404933.7	c.-92A>G		5_prime_UTR_variant	1/11	1	NM_004595.5	P1
SMS	ENST00000379404.5	c.-92A>G		5_prime_UTR_variant	1/9	3
SMS	ENST00000478094.1			upstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.348 AC: 37841 AN: 108825 Hom.: 5924 Cov.: 21 AF XY: 0.338 AC XY: 10644 AN XY: 31477

Gnomad AFR AF: 0.613

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.216

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.291

GnomAD4 exome AF: 0.245 AC: 155313 AN: 633068 Hom.: 15010 Cov.: 9 AF XY: 0.258 AC XY: 43085 AN XY: 167026

Gnomad4 AFR exome AF: 0.623

Gnomad4 AMR exome AF: 0.215

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.309

Gnomad4 SAS exome AF: 0.348

Gnomad4 FIN exome AF: 0.303

Gnomad4 NFE exome AF: 0.223

Gnomad4 OTH exome AF: 0.261

GnomAD4 genome AF: 0.348 AC: 37887 AN: 108862 Hom.: 5940 Cov.: 21 AF XY: 0.338 AC XY: 10668 AN XY: 31524

Gnomad4 AFR AF: 0.613

Gnomad4 AMR AF: 0.272

Gnomad4 ASJ AF: 0.215

Gnomad4 EAS AF: 0.319

Gnomad4 SAS AF: 0.355

Gnomad4 FIN AF: 0.278

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.299

Alfa AF: 0.282 Hom.: 1758

Bravo AF: 0.356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	14
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs34507903; hg19: chrX-21958851;