NM_004595.5:c.166G>A

Variant names:

• chrX-21967312-G-A
• rs121434610
• NM_004595.5:c.166G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_004595.5(SMS):​c.166G>A​(p.Gly56Ser) 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. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G56G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 21)
• Consequence: SMS NM_004595.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 6.92
• Publications: 29 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 13 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, 0.929
• PP5: Variant X-21967312-G-A is Pathogenic according to our data. Variant chrX-21967312-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.166G>A	p.Gly56Ser	missense	Exon 2 of 11	NP_004586.2
	SMS	NM_001258423.2		c.166G>A	p.Gly56Ser	missense	Exon 2 of 9	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.166G>A	p.Gly56Ser	missense	Exon 2 of 11	ENSP00000385746.2	P52788-1
	SMS	ENST00000853889.1		c.166G>A	p.Gly56Ser	missense	Exon 2 of 12	ENSP00000523948.1
	SMS	ENST00000955899.1		c.166G>A	p.Gly56Ser	missense	Exon 2 of 12	ENSP00000625958.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)
1	-	-	Syndromic X-linked intellectual disability Snyder type (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.061	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.63
Sift	Benign	0.096	T
Sift4G	Benign	0.18	T
Polyphen		0.42	B
Vest4		0.85
MutPred		0.73		Loss of sheet (P = 0.0357)
MVP		1.0
MPC		1.8
ClinPred		0.92	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.85
Mutation Taster		=42/58	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: rs121434610; hg19: chrX-21985430;