rs61732077

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_004595.5(SMS):c.1026A>C(p.Ser342Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00548 in 1,194,374 control chromosomes in the GnomAD database, including 12 homozygotes. There are 2,066 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 1 hom., 97 hem., cov: 23)

Exomes 𝑓: 0.0057 ( 11 hom. 1969 hem. )

Consequence

SMS
NM_004595.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.398

Publications

0 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: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant X-21992677-A-C is Benign according to our data. Variant chrX-21992677-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.398 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 97 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMS	NM_004595.5 link	c.1026A>C	p.Ser342Ser	synonymous_variant	Exon 10 of 11	ENST00000404933.7	NP_004586.2	P52788-1
SMS	NM_001258423.2 link	c.867A>C	p.Ser289Ser	synonymous_variant	Exon 8 of 9		NP_001245352.1	P52788-2
SMS	XM_005274582.3 link	c.924A>C	p.Ser308Ser	synonymous_variant	Exon 10 of 11		XP_005274639.1
SMS	XM_011545568.3 link	c.924A>C	p.Ser308Ser	synonymous_variant	Exon 10 of 11		XP_011543870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMS	ENST00000404933.7 link	c.1026A>C	p.Ser342Ser	synonymous_variant	Exon 10 of 11	1	NM_004595.5	ENSP00000385746.2		P52788-1
SMS	ENST00000379404.5 link	c.867A>C	p.Ser289Ser	synonymous_variant	Exon 8 of 9	3		ENSP00000368714.1		P52788-2

Frequencies

GnomAD3 genomes

AF:

0.00379

AC:

425

AN:

112145

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00133

Gnomad ASJ

AF:

0.00491

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000731

Gnomad FIN

AF:

0.000329

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00672

Gnomad OTH

AF:

0.00464

GnomAD2 exomes

AF:

0.00359

AC:

657

AN:

183041

AF XY:

0.00370

show subpopulations

Gnomad AFR exome

AF:

0.00122

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00281

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000562

Gnomad NFE exome

AF:

0.00655

Gnomad OTH exome

AF:

0.00487

GnomAD4 exome

AF:

0.00565

AC:

6118

AN:

1082175

Hom.:

Cov.:

AF XY:

0.00565

AC XY:

1969

AN XY:

348695

show subpopulations

African (AFR)

AF:

0.000766

AC:

AN:

26104

American (AMR)

AF:

0.00128

AC:

AN:

35172

Ashkenazi Jewish (ASJ)

AF:

0.00311

AC:

AN:

19270

East Asian (EAS)

AF:

0.00

AC:

AN:

30148

South Asian (SAS)

AF:

0.00112

AC:

AN:

53726

European-Finnish (FIN)

AF:

0.00136

AC:

AN:

40521

Middle Eastern (MID)

AF:

0.000845

AC:

AN:

3549

European-Non Finnish (NFE)

AF:

0.00686

AC:

5682

AN:

828173

Other (OTH)

AF:

0.00424

AC:

193

AN:

45512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

195

389

584

778

973

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

208

416

624

832

1040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00379

AC:

425

AN:

112199

Hom.:

Cov.:

AF XY:

0.00282

AC XY:

AN XY:

34367

show subpopulations

African (AFR)

AF:

0.000939

AC:

AN:

30882

American (AMR)

AF:

0.00132

AC:

AN:

10578

Ashkenazi Jewish (ASJ)

AF:

0.00491

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3579

South Asian (SAS)

AF:

0.000733

AC:

AN:

2727

European-Finnish (FIN)

AF:

0.000329

AC:

AN:

6080

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00672

AC:

358

AN:

53275

Other (OTH)

AF:

0.00458

AC:

AN:

1527

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00553

Hom.:

Bravo

AF:

0.00380

EpiCase

AF:

0.00689

EpiControl

AF:

0.00634

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

May 15, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 25, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Syndromic X-linked intellectual disability Snyder type

Benign:2

Dec 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Oct 11, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SMS-related disorder

Benign:1

May 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.11

(source)

DANN

Benign

0.65

PhyloP100

-0.40

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over