Genetic Variant SMS:p.Tyr328Ser (chrX-21992634-A-C) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PM5PP2PP3_Moderate

The NM_004595.5(SMS):c.983A>C(p.Tyr328Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y328C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

SMS
NM_004595.5 missense

Scores

Clinical Significance

Not reported in ClinVar

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: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: 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.

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, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SMS	NM_004595.5 link	c.983A>C	p.Tyr328Ser	missense_variant	Exon 10 of 11	ENST00000404933.7	NP_004586.2
SMS	NM_001258423.2 link	c.824A>C	p.Tyr275Ser	missense_variant	Exon 8 of 9		NP_001245352.1
SMS	XM_005274582.3 link	c.881A>C	p.Tyr294Ser	missense_variant	Exon 10 of 11		XP_005274639.1
SMS	XM_011545568.3 link	c.881A>C	p.Tyr294Ser	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>C	p.Tyr328Ser	missense_variant	Exon 10 of 11	1	NM_004595.5	ENSP00000385746.2
SMS	ENST00000379404.5 link	c.824A>C	p.Tyr275Ser	missense_variant	Exon 8 of 9	3		ENSP00000368714.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;.

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.013

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

6.4

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-7.8

D;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.014

D;T

Polyphen

1.0

D;.

Vest4

0.73

MutPred

0.62

Gain of disorder (P = 0.0017);.;

MVP

0.98

MPC

2.3

ClinPred

1.0

GERP RS

5.6

Varity_R

0.97

gMVP

0.98

Mutation Taster

=4/96

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over