rs2040357

Variant names:

• chrX-21960709-C-T
• rs2040357
• NM_004595.5:c.50-6487C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004595.5(SMS):​c.50-6487C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 110,642 control chromosomes in the GnomAD database, including 9,449 homozygotes. There are 14,252 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.45 (9449 hom., 14252 hem., cov: 23)
• Consequence: SMS NM_004595.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.735
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

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.50-6487C>T		intron	N/A	NP_004586.2
	SMS	NM_001258423.2		c.50-6487C>T		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.50-6487C>T		intron	N/A	ENSP00000385746.2	P52788-1
	SMS	ENST00000853889.1		c.50-6487C>T		intron	N/A	ENSP00000523948.1
	SMS	ENST00000955899.1		c.50-6487C>T		intron	N/A	ENSP00000625958.1

Frequencies

GnomAD3 genomes AF: 0.446 AC: 49373 AN: 110594 Hom.: 9438 Cov.: 23

Gnomad AFR AF: 0.747

Gnomad AMI AF: 0.290

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.421

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.447 AC: 49425 AN: 110642 Hom.: 9449 Cov.: 23 AF XY: 0.433 AC XY: 14252 AN XY: 32896

African (AFR) AF: 0.747 AC: 22654 AN: 30321

American (AMR) AF: 0.469 AC: 4861 AN: 10363

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 973 AN: 2632

East Asian (EAS) AF: 0.308 AC: 1079 AN: 3500

South Asian (SAS) AF: 0.172 AC: 461 AN: 2674

European-Finnish (FIN) AF: 0.329 AC: 1933 AN: 5878

Middle Eastern (MID) AF: 0.349 AC: 74 AN: 212

European-Non Finnish (NFE) AF: 0.313 AC: 16559 AN: 52891

Other (OTH) AF: 0.424 AC: 636 AN: 1499

Alfa AF: 0.389 Hom.: 3264

Bravo AF: 0.476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.80
DANN	Benign	0.55
PhyloP100		-0.73
Mutation Taster		=100/0	polymorphism (auto)

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: rs2040357; hg19: chrX-21978827;