NM_004595.5:c.638C>A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2PP2PP3_StrongPP5_Moderate

The NM_004595.5(SMS):c.638C>A(p.Pro213Gln) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P213S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

SMS
NM_004595.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.57

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: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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, 0.965

PP5

Variant X-21978092-C-A is Pathogenic according to our data. Variant chrX-21978092-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 520793.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.638C>A	p.Pro213Gln	missense_variant	Exon 6 of 11	ENST00000404933.7	NP_004586.2	P52788-1
SMS	NM_001258423.2 link	c.479C>A	p.Pro160Gln	missense_variant	Exon 4 of 9		NP_001245352.1	P52788-2
SMS	XM_005274582.3 link	c.536C>A	p.Pro179Gln	missense_variant	Exon 6 of 11		XP_005274639.1
SMS	XM_011545568.3 link	c.536C>A	p.Pro179Gln	missense_variant	Exon 6 of 11		XP_011543870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMS	ENST00000404933.7 link	c.638C>A	p.Pro213Gln	missense_variant	Exon 6 of 11	1	NM_004595.5	ENSP00000385746.2	P52788-1
SMS	ENST00000457085.2 link	c.983C>A	p.Pro328Gln	missense_variant	Exon 6 of 6	5		ENSP00000407366.2	H7C2R7
SMS	ENST00000379404.5 link	c.479C>A	p.Pro160Gln	missense_variant	Exon 4 of 9	3		ENSP00000368714.1	P52788-2
SMS	ENST00000478094.1 link	n.*103C>A		downstream_gene_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

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

AF:

0.00

AC:

AN:

1095491

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360921

African (AFR)

AF:

0.00

AC:

AN:

26351

American (AMR)

AF:

0.00

AC:

AN:

35199

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19367

East Asian (EAS)

AF:

0.00

AC:

AN:

30188

South Asian (SAS)

AF:

0.00

AC:

AN:

54084

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4128

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

839645

Other (OTH)

AF:

0.00

AC:

AN:

46007

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Apr 18, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.638C>A (p.P213Q) alteration is located in exon 6 of the SMS gene. This alteration results from a C to A substitution at nucleotide position 638, causing the proline (P) at amino acid position 213 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

T;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.33

MutationAssessor

Benign

2.0

M;.

PhyloP100

7.6

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.7

D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.81

MutPred

0.79

Loss of catalytic residue at K212 (P = 0.1105);.;

MVP

0.89

MPC

2.0

ClinPred

1.0

GERP RS

5.6

Varity_R

0.93

gMVP

0.97

Mutation Taster

=12/88

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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