X-21967260-G-A

Variant names:

• chrX-21967260-G-A
• rs138924455
• NM_004595.5:c.114G>A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004595.5(SMS):​c.114G>A​(p.Ser38Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,206,228 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 42 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 0.00013 (0 hom., 2 hem., cov: 21)
  • Exomes 𝑓: 0.00013 (0 hom. 40 hem.)
• Consequence: SMS NM_004595.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.466

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant X-21967260-G-A is Benign according to our data. Variant chrX-21967260-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 589182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.466 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMS	NM_004595.5	c.114G>A	p.Ser38Ser	synonymous_variant	Exon 2 of 11	ENST00000404933.7	NP_004586.2
SMS	NM_001258423.2	c.114G>A	p.Ser38Ser	synonymous_variant	Exon 2 of 9		NP_001245352.1
SMS	XM_005274582.3	c.12G>A	p.Ser4Ser	synonymous_variant	Exon 2 of 11		XP_005274639.1
SMS	XM_011545568.3	c.12G>A	p.Ser4Ser	synonymous_variant	Exon 2 of 11		XP_011543870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMS	ENST00000404933.7	c.114G>A	p.Ser38Ser	synonymous_variant	Exon 2 of 11	1	NM_004595.5	ENSP00000385746.2
SMS	ENST00000457085.2	c.459G>A	p.Ser153Ser	synonymous_variant	Exon 2 of 6	5		ENSP00000407366.2
SMS	ENST00000379404.5	c.114G>A	p.Ser38Ser	synonymous_variant	Exon 2 of 9	3		ENSP00000368714.1
SMS	ENST00000478094.1	n.161G>A		non_coding_transcript_exon_variant	Exon 2 of 5	4

Frequencies

GnomAD3 genomes AF: 0.000128 AC: 14 AN: 109513 Hom.: 0 Cov.: 21 AF XY: 0.0000629 AC XY: 2 AN XY: 31785

Gnomad AFR AF: 0.000100

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: 0.000209

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000764 AC: 14 AN: 183292 Hom.: 0 AF XY: 0.0000590 AC XY: 4 AN XY: 67748

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.0000729

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: 0.000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000131 AC: 144 AN: 1096715 Hom.: 0 Cov.: 29 AF XY: 0.000110 AC XY: 40 AN XY: 362117

Gnomad4 AFR exome AF: 0.000265

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000149

Gnomad4 OTH exome AF: 0.000196

GnomAD4 genome AF: 0.000128 AC: 14 AN: 109513 Hom.: 0 Cov.: 21 AF XY: 0.0000629 AC XY: 2 AN XY: 31785

Gnomad4 AFR AF: 0.000100

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000209

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000304 Hom.: 3

Bravo AF: 0.000174

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

May 30, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

Jun 04, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Syndromic X-linked intellectual disability Snyder type Benign:1

Dec 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.5
DANN	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs138924455; hg19: chrX-21985378;