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:

Genome browser will be placed here

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SMS	NM_004595.5 link	c.983A>G	p.Tyr328Cys	missense_variant	Exon 10 of 11	ENST00000404933.7	NP_004586.2
SMS	NM_001258423.2 link	c.824A>G	p.Tyr275Cys	missense_variant	Exon 8 of 9		NP_001245352.1
SMS	XM_005274582.3 link	c.881A>G	p.Tyr294Cys	missense_variant	Exon 10 of 11		XP_005274639.1
SMS	XM_011545568.3 link	c.881A>G	p.Tyr294Cys	missense_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.983A>G	p.Tyr328Cys	missense_variant	Exon 10 of 11	1	NM_004595.5	ENSP00000385746.2
SMS	ENST00000379404.5 link	c.824A>G	p.Tyr275Cys	missense_variant	Exon 8 of 9	3		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 v4.3

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

T;.

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Uncertain

0.30

MutationAssessor

Uncertain

2.4

M;.

PhyloP100

6.4

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-7.9

D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.029

D;D

Vest4

0.93

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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