rs5951676

Variant names:

• chrX-21986710-A-G
• rs5951676
• NM_004595.5:c.945+1487A>G

Variant summary

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

The NM_004595.5(SMS):​c.945+1487A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 112,061 control chromosomes in the GnomAD database, including 1,559 homozygotes. There are 4,266 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 (1559 hom., 4266 hem., cov: 24)
• Consequence: SMS NM_004595.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.241
• 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMS	NM_004595.5	c.945+1487A>G		intron_variant	Intron 9 of 10	ENST00000404933.7	NP_004586.2
SMS	NM_001258423.2	c.786+1487A>G		intron_variant	Intron 7 of 8		NP_001245352.1
SMS	XM_005274582.3	c.843+1487A>G		intron_variant	Intron 9 of 10		XP_005274639.1
SMS	XM_011545568.3	c.843+1487A>G		intron_variant	Intron 9 of 10		XP_011543870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMS	ENST00000404933.7	c.945+1487A>G		intron_variant	Intron 9 of 10	1	NM_004595.5	ENSP00000385746.2
SMS	ENST00000379404.5	c.786+1487A>G		intron_variant	Intron 7 of 8	3		ENSP00000368714.1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 15236 AN: 112006 Hom.: 1556 Cov.: 24

Gnomad AFR AF: 0.353

Gnomad AMI AF: 0.00146

Gnomad AMR AF: 0.0769

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.00864

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0441

Gnomad MID AF: 0.0847

Gnomad NFE AF: 0.0483

Gnomad OTH AF: 0.112

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

GnomAD4 genome AF: 0.136 AC: 15255 AN: 112061 Hom.: 1559 Cov.: 24 AF XY: 0.125 AC XY: 4266 AN XY: 34263

African (AFR) AF: 0.352 AC: 10807 AN: 30697

American (AMR) AF: 0.0767 AC: 812 AN: 10586

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 281 AN: 2655

East Asian (EAS) AF: 0.00866 AC: 31 AN: 3578

South Asian (SAS) AF: 0.105 AC: 288 AN: 2752

European-Finnish (FIN) AF: 0.0441 AC: 269 AN: 6097

Middle Eastern (MID) AF: 0.0744 AC: 16 AN: 215

European-Non Finnish (NFE) AF: 0.0483 AC: 2571 AN: 53285

Other (OTH) AF: 0.119 AC: 179 AN: 1510

Alfa AF: 0.104 Hom.: 720

Bravo AF: 0.148

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.7
DANN	Benign	0.47
PhyloP100		-0.24
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: rs5951676; hg19: chrX-22004828;