NM_004595.5:c.45C>G

Variant names:

• chrX-21940869-C-G
• rs1300131974
• NM_004595.5:c.45C>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_004595.5(SMS):​c.45C>G​(p.Ala15Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 1,095,785 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000010 (0 hom. 2 hem.)
• Consequence: SMS NM_004595.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0990
• Publications: 0 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant X-21940869-C-G is Benign according to our data. Variant chrX-21940869-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 792193.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.099 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 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.45C>G	p.Ala15Ala	synonymous	Exon 1 of 11	NP_004586.2
	SMS	NM_001258423.2		c.45C>G	p.Ala15Ala	synonymous	Exon 1 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.45C>G	p.Ala15Ala	synonymous	Exon 1 of 11	ENSP00000385746.2	P52788-1
	SMS	ENST00000853889.1		c.45C>G	p.Ala15Ala	synonymous	Exon 1 of 12	ENSP00000523948.1
	SMS	ENST00000955899.1		c.45C>G	p.Ala15Ala	synonymous	Exon 1 of 12	ENSP00000625958.1

Frequencies

GnomAD3 genomes AF: 0.0000365 AC: 4 AN: 109594 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 65135 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000101 AC: 10 AN: 986191 Hom.: 0 Cov.: 27 AF XY: 0.00000638 AC XY: 2 AN XY: 313293

African (AFR) AF: 0.000386 AC: 8 AN: 20707

American (AMR) AF: 0.0000433 AC: 1 AN: 23121

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16706

East Asian (EAS) AF: 0.00 AC: 0 AN: 21683

South Asian (SAS) AF: 0.00 AC: 0 AN: 45901

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24741

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2644

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 789600

Other (OTH) AF: 0.0000243 AC: 1 AN: 41088

GnomAD4 genome AF: 0.0000365 AC: 4 AN: 109594 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 32514

African (AFR) AF: 0.000131 AC: 4 AN: 30543

American (AMR) AF: 0.00 AC: 0 AN: 10567

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2590

East Asian (EAS) AF: 0.00 AC: 0 AN: 3416

South Asian (SAS) AF: 0.00 AC: 0 AN: 2707

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5601

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 233

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 51804

Other (OTH) AF: 0.00 AC: 0 AN: 1477

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000102

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	15
DANN	Benign	0.84
PhyloP100		-0.099
PromoterAI		-0.054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1300131974; hg19: chrX-21958987;