dbSNP rs397515381: SMS:c.329+5G>A (chrX-21972576-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3PP5

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:1O:1

Conservation

PhyloP100: 4.89

Publications

4 publications found

Variant links:

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]

SMS Gene-Disease associations (from GenCC):

syndromic X-linked intellectual disability Snyder type
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P

SMS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious 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 VariationId is 11623.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SMS	NM_004595.5 link	c.329+5G>A	splice_region_variant, intron_variant	Intron 4 of 10	ENST00000404933.7	NP_004586.2	P52788-1
SMS	NM_001258423.2 link	c.171-4485G>A	intron_variant	Intron 2 of 8		NP_001245352.1	P52788-2
SMS	XM_005274582.3 link	c.227+5G>A	splice_region_variant, intron_variant	Intron 4 of 10		XP_005274639.1
SMS	XM_011545568.3 link	c.227+5G>A	splice_region_variant, intron_variant	Intron 4 of 10		XP_011543870.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMS	ENST00000404933.7 link	c.329+5G>A	splice_region_variant, intron_variant	Intron 4 of 10	1	NM_004595.5	ENSP00000385746.2	P52788-1
SMS	ENST00000457085.2 link	c.674+5G>A	splice_region_variant, intron_variant	Intron 4 of 5	5		ENSP00000407366.2	H7C2R7
SMS	ENST00000379404.5 link	c.171-4485G>A	intron_variant	Intron 2 of 8	3		ENSP00000368714.1	P52788-2
SMS	ENST00000478094.1 link	n.282+5G>A	splice_region_variant, intron_variant	Intron 3 of 4	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1026712

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

304700

African (AFR)

AF:

0.00

AC:

AN:

25075

American (AMR)

AF:

0.00

AC:

AN:

35117

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18962

East Asian (EAS)

AF:

0.00

AC:

AN:

29943

South Asian (SAS)

AF:

0.00

AC:

AN:

52459

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40486

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3797

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

777099

Other (OTH)

AF:

0.00

AC:

AN:

43774

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Syndromic X-linked intellectual disability Snyder type

Pathogenic:1Other: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

(source)

DANN

Benign

0.88

PhyloP100

4.9

Mutation Taster

=12/88

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over