NM_004595.5:c.443A>G

Variant names:

• chrX-21977174-A-G
• rs397515551
• NM_004595.5:c.443A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP2 PP3_Strong PP5

The NM_004595.5(SMS):​c.443A>G​(p.Gln148Arg) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q148E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: SMS NM_004595.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 8.90
• Publications: 9 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 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-21977173-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4279691.Status of the report is criteria_provided_single_submitter, 1 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, 0.989
• PP5: Variant X-21977174-A-G is Pathogenic according to our data. Variant chrX-21977174-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 65679.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMS	NM_004595.5	c.443A>G	p.Gln148Arg	missense_variant	Exon 5 of 11	ENST00000404933.7	NP_004586.2
SMS	NM_001258423.2	c.284A>G	p.Gln95Arg	missense_variant	Exon 3 of 9		NP_001245352.1
SMS	XM_005274582.3	c.341A>G	p.Gln114Arg	missense_variant	Exon 5 of 11		XP_005274639.1
SMS	XM_011545568.3	c.341A>G	p.Gln114Arg	missense_variant	Exon 5 of 11		XP_011543870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMS	ENST00000404933.7	c.443A>G	p.Gln148Arg	missense_variant	Exon 5 of 11	1	NM_004595.5	ENSP00000385746.2
SMS	ENST00000457085.2	c.788A>G	p.Gln263Arg	missense_variant	Exon 5 of 6	5		ENSP00000407366.2
SMS	ENST00000379404.5	c.284A>G	p.Gln95Arg	missense_variant	Exon 3 of 9	3		ENSP00000368714.1
SMS	ENST00000478094.1	n.396A>G		non_coding_transcript_exon_variant	Exon 4 of 5	4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Syndromic X-linked intellectual disability Snyder type Pathogenic:1 Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Undiagnosed Diseases Program Translational Research Laboratory, National Institutes of Health

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.3	M;.
PhyloP100		8.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.90		Gain of ubiquitination at K151 (P = 0.1222);.;
MVP		1.0
MPC		1.9
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.96
gMVP		1.0
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397515551; hg19: chrX-21995292; COSMIC: COSV65114197;