dbSNP rs397515550: SMS:p.Gly67Glu (chrX-21971926-G-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_004595.5(SMS):c.200G>A(p.Gly67Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

SMS
NM_004595.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 8.22

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

PP5

Variant X-21971926-G-A is Pathogenic according to our data. Variant chrX-21971926-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 65677.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMS	NM_004595.5 link	c.200G>A	p.Gly67Glu	missense_variant	Exon 3 of 11	ENST00000404933.7	NP_004586.2	P52788-1
SMS	XM_005274582.3 link	c.98G>A	p.Gly33Glu	missense_variant	Exon 3 of 11		XP_005274639.1
SMS	XM_011545568.3 link	c.98G>A	p.Gly33Glu	missense_variant	Exon 3 of 11		XP_011543870.1
SMS	NM_001258423.2 link	c.170+4610G>A		intron_variant	Intron 2 of 8		NP_001245352.1	P52788-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMS	ENST00000404933.7 link	c.200G>A	p.Gly67Glu	missense_variant	Exon 3 of 11	1	NM_004595.5	ENSP00000385746.2	P52788-1
SMS	ENST00000457085.2 link	c.545G>A	p.Gly182Glu	missense_variant	Exon 3 of 6	5		ENSP00000407366.2	H7C2R7
SMS	ENST00000379404.5 link	c.170+4610G>A		intron_variant	Intron 2 of 8	3		ENSP00000368714.1	P52788-2
SMS	ENST00000478094.1 link	n.218-581G>A		intron_variant	Intron 2 of 4	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1087029

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

353327

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.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Oct 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest a damaging effect resulting in low levels of protein (Peng et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23897707, 26761001) -

Syndromic X-linked intellectual disability Snyder type

Pathogenic:1

Sep 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.96

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-4.4

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0020

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.97

MutPred

0.76

Gain of sheet (P = 0.0101);

MVP

0.99

MPC

2.1

ClinPred

0.99

GERP RS

5.7

Varity_R

0.95

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over