NM_004595.5:c.200G>A

Variant names:

• chrX-21971926-G-A
• rs397515550
• NM_004595.5:c.200G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_004595.5(SMS):​c.200G>A​(p.Gly67Glu) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G67V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SMS NM_004595.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.22
• Publications: 4 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), PanelApp Australia, Orphanet, G2P, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 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-21971926-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2630815.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, 0.965
• PP5: Variant X-21971926-G-A is Pathogenic according to our data. Variant chrX-21971926-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 65677.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMS	NM_004595.5	MANE Select	c.200G>A	p.Gly67Glu	missense	Exon 3 of 11	NP_004586.2
	SMS	NM_001258423.2		c.170+4610G>A		intron	N/A	NP_001245352.1	P52788-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMS	ENST00000404933.7	TSL:1 MANE Select	c.200G>A	p.Gly67Glu	missense	Exon 3 of 11	ENSP00000385746.2	P52788-1
	SMS	ENST00000853889.1		c.200G>A	p.Gly67Glu	missense	Exon 3 of 12	ENSP00000523948.1
	SMS	ENST00000955899.1		c.200G>A	p.Gly67Glu	missense	Exon 3 of 12	ENSP00000625958.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1087029 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 353327

African (AFR) AF: 0.00 AC: 0 AN: 26206

American (AMR) AF: 0.00 AC: 0 AN: 35190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19301

East Asian (EAS) AF: 0.00 AC: 0 AN: 30171

South Asian (SAS) AF: 0.00 AC: 0 AN: 53877

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40529

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3663

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 832360

Other (OTH) AF: 0.00 AC: 0 AN: 45732

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Syndromic X-linked intellectual disability Snyder type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		8.2
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.97
MutPred		0.76		Gain of sheet (P = 0.0101)
MVP		0.99
MPC		2.1
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.95
gMVP		0.98
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs397515550; hg19: chrX-21990044;