rs760174828

chrX-21978930-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_004595.5(SMS):c.714C>T(p.Gly238=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000432 in 1,203,090 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000043 (0 hom. 14 hem.)
• Consequence: SMS NM_004595.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.634

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant X-21978930-C-T is Benign according to our data. Variant chrX-21978930-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212275.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BP7: Synonymous conserved (PhyloP=-0.634 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMS	NM_004595.5	c.714C>T	p.Gly238=	synonymous_variant	7/11	ENST00000404933.7
SMS	NM_001258423.2	c.555C>T	p.Gly185=	synonymous_variant	5/9
SMS	XM_005274582.3	c.612C>T	p.Gly204=	synonymous_variant	7/11
SMS	XM_011545568.3	c.612C>T	p.Gly204=	synonymous_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMS	ENST00000404933.7	c.714C>T	p.Gly238=	synonymous_variant	7/11	1	NM_004595.5	P1
SMS	ENST00000379404.5	c.555C>T	p.Gly185=	synonymous_variant	5/9	3

Frequencies

GnomAD3 genomes AF: 0.0000357 AC: 4 AN: 112030 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34230

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000947

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: 0.0000188

Gnomad OTH AF: 0.000672

GnomAD3 exomes AF: 0.000131 AC: 24 AN: 183335 Hom.: 0 AF XY: 0.000118 AC XY: 8 AN XY: 67811

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.000802

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 47 AN: 1091010 Hom.: 0 Cov.: 28 AF XY: 0.0000392 AC XY: 14 AN XY: 356724

Gnomad4 AFR exome AF: 0.0000761

Gnomad4 AMR exome AF: 0.000682

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000227

Gnomad4 OTH exome AF: 0.0000436

GnomAD4 genome AF: 0.0000446 AC: 5 AN: 112080 Hom.: 0 Cov.: 23 AF XY: 0.0000292 AC XY: 1 AN XY: 34290

Gnomad4 AFR AF: 0.0000648

Gnomad4 AMR AF: 0.0000946

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.000664

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000604

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 29, 2015

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	1.4
Dann	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs760174828; hg19: chrX-21997048;