rs397515381

Variant names:

• chrX-21972576-G-A
• rs397515381
• NM_004595.5:c.329+5G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_004595.5(SMS):​c.329+5G>A variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SMS NM_004595.5 splice_region, intron
• Scores: Splicing: ADA: 0.9719
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 4.89

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-21972576-G-A is Pathogenic according to our data. Variant chrX-21972576-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11623.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMS	NM_004595.5	c.329+5G>A		splice_region_variant, intron_variant	Intron 4 of 10	ENST00000404933.7	NP_004586.2
SMS	NM_001258423.2	c.171-4485G>A		intron_variant	Intron 2 of 8		NP_001245352.1
SMS	XM_005274582.3	c.227+5G>A		splice_region_variant, intron_variant	Intron 4 of 10		XP_005274639.1
SMS	XM_011545568.3	c.227+5G>A		splice_region_variant, intron_variant	Intron 4 of 10		XP_011543870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMS	ENST00000404933.7	c.329+5G>A		splice_region_variant, intron_variant	Intron 4 of 10	1	NM_004595.5	ENSP00000385746.2
SMS	ENST00000457085.2	c.674+5G>A		splice_region_variant, intron_variant	Intron 4 of 5	5		ENSP00000407366.2
SMS	ENST00000379404.5	c.171-4485G>A		intron_variant	Intron 2 of 8	3		ENSP00000368714.1
SMS	ENST00000478094.1	n.282+5G>A		splice_region_variant, intron_variant	Intron 3 of 4	4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1026712 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 304700

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Syndromic X-linked intellectual disability Snyder type Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.86		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.86		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397515381; hg19: chrX-21990694;