NM_004595.5:c.49+8566C>T

Variant names:

• chrX-21949439-C-T
• rs5951672
• NM_004595.5:c.49+8566C>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.49+8566C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 111,583 control chromosomes in the GnomAD database, including 1,801 homozygotes. There are 4,444 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 0.14 (1801 hom., 4444 hem., cov: 23)
• Consequence: SMS NM_004595.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.675
• 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), Orphanet, ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.379 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMS	NM_004595.5	MANE Select	c.49+8566C>T		intron	N/A	NP_004586.2
	SMS	NM_001258423.2		c.49+8566C>T		intron	N/A	NP_001245352.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMS	ENST00000404933.7	TSL:1 MANE Select	c.49+8566C>T		intron	N/A	ENSP00000385746.2
	SMS	ENST00000457085.2	TSL:5	c.394+8072C>T		intron	N/A	ENSP00000407366.2
	SMS	ENST00000379404.5	TSL:3	c.49+8566C>T		intron	N/A	ENSP00000368714.1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 16064 AN: 111531 Hom.: 1796 Cov.: 23

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.00292

Gnomad AMR AF: 0.0843

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.00811

Gnomad SAS AF: 0.0723

Gnomad FIN AF: 0.0464

Gnomad MID AF: 0.105

Gnomad NFE AF: 0.0465

Gnomad OTH AF: 0.125

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

GnomAD4 genome AF: 0.144 AC: 16093 AN: 111583 Hom.: 1801 Cov.: 23 AF XY: 0.131 AC XY: 4444 AN XY: 33809

African (AFR) AF: 0.385 AC: 11740 AN: 30526

American (AMR) AF: 0.0841 AC: 887 AN: 10547

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 268 AN: 2639

East Asian (EAS) AF: 0.00813 AC: 29 AN: 3568

South Asian (SAS) AF: 0.0725 AC: 196 AN: 2702

European-Finnish (FIN) AF: 0.0464 AC: 278 AN: 5996

Middle Eastern (MID) AF: 0.101 AC: 22 AN: 218

European-Non Finnish (NFE) AF: 0.0465 AC: 2472 AN: 53181

Other (OTH) AF: 0.131 AC: 199 AN: 1521

Alfa AF: 0.167 Hom.: 3131

Bravo AF: 0.158

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Benign	0.61
PhyloP100		0.68
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: rs5951672; hg19: chrX-21967557;