Genetic Variant SMS:p.Tyr328Cys (chrX-21992634-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP2PP3_ModeratePP5BS2

The NM_004595.5(SMS):c.983A>G(p.Tyr328Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000183 in 1,092,446 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 2 hem. )

Consequence

SMS
NM_004595.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.42

Publications

15 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 19 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 2.3162 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to syndromic X-linked intellectual disability Snyder type.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.924

PP5

Variant X-21992634-A-G is Pathogenic according to our data. Variant chrX-21992634-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 88767.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004595.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMS	NM_004595.5	MANE Select	c.983A>G	p.Tyr328Cys	missense	Exon 10 of 11	NP_004586.2
	SMS	NM_001258423.2		c.824A>G	p.Tyr275Cys	missense	Exon 8 of 9	NP_001245352.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMS	ENST00000404933.7	TSL:1 MANE Select	c.983A>G	p.Tyr328Cys	missense	Exon 10 of 11	ENSP00000385746.2
	SMS	ENST00000379404.5	TSL:3	c.824A>G	p.Tyr275Cys	missense	Exon 8 of 9	ENSP00000368714.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000183

AC:

AN:

1092446

Hom.:

Cov.:

AF XY:

0.00000557

AC XY:

AN XY:

358948

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26285

American (AMR)

AF:

0.00

AC:

AN:

35193

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19354

East Asian (EAS)

AF:

0.00

AC:

AN:

30183

South Asian (SAS)

AF:

0.00

AC:

AN:

53980

European-Finnish (FIN)

AF:

0.0000247

AC:

AN:

40532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3005

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

838084

Other (OTH)

AF:

0.00

AC:

AN:

45830

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Syndromic X-linked intellectual disability Snyder type

Pathogenic:1

Sep 15, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.30

MutationAssessor

Uncertain

2.4

PhyloP100

6.4

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-7.9

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.029

Polyphen

1.0

Vest4

0.93

MutPred

0.58

Gain of catalytic residue at E330 (P = 0.2379)

MVP

0.98

MPC

1.9

ClinPred

1.0

GERP RS

5.6

Varity_R

0.94

gMVP

0.97

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over