chrX-21967259-C-T

Variant names:

• chrX-21967259-C-T
• rs377476289
• NM_004595.5:c.113C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_004595.5(SMS):​c.113C>T​(p.Ser38Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000448 in 1,205,657 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S38S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., 2 hem., cov: 21)
  • Exomes 𝑓: 0.000045 (0 hom. 17 hem.)
• Consequence: SMS NM_004595.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.10
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32761014).
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

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.113C>T	p.Ser38Leu	missense	Exon 2 of 11	NP_004586.2
	SMS	NM_001258423.2		c.113C>T	p.Ser38Leu	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.113C>T	p.Ser38Leu	missense	Exon 2 of 11	ENSP00000385746.2	P52788-1
	SMS	ENST00000853889.1		c.113C>T	p.Ser38Leu	missense	Exon 2 of 12	ENSP00000523948.1
	SMS	ENST00000955899.1		c.113C>T	p.Ser38Leu	missense	Exon 2 of 12	ENSP00000625958.1

Frequencies

GnomAD3 genomes AF: 0.0000456 AC: 5 AN: 109538 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000948

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000327 AC: 6 AN: 183296 AF XY: 0.0000443

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000216

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000447 AC: 49 AN: 1096119 Hom.: 0 Cov.: 29 AF XY: 0.0000470 AC XY: 17 AN XY: 361557

African (AFR) AF: 0.0000380 AC: 1 AN: 26345

American (AMR) AF: 0.00 AC: 0 AN: 35187

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19358

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30155

South Asian (SAS) AF: 0.00 AC: 0 AN: 54100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40437

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4038

European-Non Finnish (NFE) AF: 0.0000512 AC: 43 AN: 840507

Other (OTH) AF: 0.0000870 AC: 4 AN: 45992

GnomAD4 genome AF: 0.0000456 AC: 5 AN: 109538 Hom.: 0 Cov.: 21 AF XY: 0.0000629 AC XY: 2 AN XY: 31776

African (AFR) AF: 0.00 AC: 0 AN: 30015

American (AMR) AF: 0.00 AC: 0 AN: 10116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2628

East Asian (EAS) AF: 0.00 AC: 0 AN: 3520

South Asian (SAS) AF: 0.00 AC: 0 AN: 2529

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.0000948 AC: 5 AN: 52733

Other (OTH) AF: 0.00 AC: 0 AN: 1463

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000327

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Syndromic X-linked intellectual disability Snyder type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.28
Sift	Benign	0.065	T
Sift4G	Benign	0.26	T
Polyphen		0.0030	B
Vest4		0.38
MVP		0.78
MPC		0.80
ClinPred		0.083	T
GERP RS		5.3
Varity_R		0.41
gMVP		0.53
Mutation Taster		=81/19	polymorphism

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: rs377476289; hg19: chrX-21985377;