NM_004595.5:c.751-623G>A

Variant names:

• chrX-21983681-G-A
• rs10521911
• NM_004595.5:c.751-623G>A

Variant summary

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

The NM_004595.5(SMS):​c.751-623G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 110,107 control chromosomes in the GnomAD database, including 2,145 homozygotes. There are 6,405 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 0.21 (2145 hom., 6405 hem., cov: 22)
• Consequence: SMS NM_004595.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.37
• 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMS	NM_004595.5	c.751-623G>A		intron_variant	Intron 7 of 10	ENST00000404933.7	NP_004586.2
SMS	NM_001258423.2	c.592-623G>A		intron_variant	Intron 5 of 8		NP_001245352.1
SMS	XM_005274582.3	c.649-623G>A		intron_variant	Intron 7 of 10		XP_005274639.1
SMS	XM_011545568.3	c.649-623G>A		intron_variant	Intron 7 of 10		XP_011543870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMS	ENST00000404933.7	c.751-623G>A		intron_variant	Intron 7 of 10	1	NM_004595.5	ENSP00000385746.2
SMS	ENST00000379404.5	c.592-623G>A		intron_variant	Intron 5 of 8	3		ENSP00000368714.1

Frequencies

GnomAD3 genomes AF: 0.209 AC: 22997 AN: 110053 Hom.: 2142 Cov.: 22

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.0602

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.153

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.182

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

GnomAD4 genome AF: 0.209 AC: 23033 AN: 110107 Hom.: 2145 Cov.: 22 AF XY: 0.197 AC XY: 6405 AN XY: 32435

African (AFR) AF: 0.347 AC: 10489 AN: 30193

American (AMR) AF: 0.131 AC: 1349 AN: 10268

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 392 AN: 2627

East Asian (EAS) AF: 0.145 AC: 504 AN: 3485

South Asian (SAS) AF: 0.0596 AC: 157 AN: 2634

European-Finnish (FIN) AF: 0.162 AC: 925 AN: 5698

Middle Eastern (MID) AF: 0.158 AC: 34 AN: 215

European-Non Finnish (NFE) AF: 0.167 AC: 8793 AN: 52802

Other (OTH) AF: 0.179 AC: 270 AN: 1507

Alfa AF: 0.188 Hom.: 3272

Bravo AF: 0.218

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.12
DANN	Benign	0.38
PhyloP100		-1.4
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: rs10521911; hg19: chrX-22001799;