X-21967346-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004595.5(SMS):c.170+30C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,199,814 control chromosomes in the GnomAD database, including 62,811 homozygotes. There are 138,191 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (12113 hom., 14863 hem., cov: 21)
  • Exomes 𝑓: 0.35 (50698 hom. 123328 hem.)
• Consequence: SMS NM_004595.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.133

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant X-21967346-C-T is Benign according to our data. Variant chrX-21967346-C-T is described in ClinVar as [Benign]. Clinvar id is 1298254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.861 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMS	NM_004595.5	c.170+30C>T		intron_variant		ENST00000404933.7
SMS	NM_001258423.2	c.170+30C>T		intron_variant
SMS	XM_005274582.3	c.68+30C>T		intron_variant
SMS	XM_011545568.3	c.68+30C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMS	ENST00000404933.7	c.170+30C>T		intron_variant		1	NM_004595.5	P1
SMS	ENST00000379404.5	c.170+30C>T		intron_variant		3
SMS	ENST00000457085.2	c.515+30C>T		intron_variant		5
SMS	ENST00000478094.1	n.217+30C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.496 AC: 53980 AN: 108844 Hom.: 12101 Cov.: 21 AF XY: 0.475 AC XY: 14808 AN XY: 31174

Gnomad AFR AF: 0.869

Gnomad AMI AF: 0.291

Gnomad AMR AF: 0.495

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.376

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.459

GnomAD3 exomes AF: 0.386 AC: 70063 AN: 181683 Hom.: 10861 AF XY: 0.354 AC XY: 23551 AN XY: 66569

Gnomad AFR exome AF: 0.884

Gnomad AMR exome AF: 0.460

Gnomad ASJ exome AF: 0.402

Gnomad EAS exome AF: 0.322

Gnomad SAS exome AF: 0.209

Gnomad FIN exome AF: 0.357

Gnomad NFE exome AF: 0.336

Gnomad OTH exome AF: 0.389

GnomAD4 exome AF: 0.354 AC: 385999 AN: 1090918 Hom.: 50698 Cov.: 29 AF XY: 0.345 AC XY: 123328 AN XY: 357224

Gnomad4 AFR exome AF: 0.888

Gnomad4 AMR exome AF: 0.467

Gnomad4 ASJ exome AF: 0.410

Gnomad4 EAS exome AF: 0.312

Gnomad4 SAS exome AF: 0.219

Gnomad4 FIN exome AF: 0.357

Gnomad4 NFE exome AF: 0.340

Gnomad4 OTH exome AF: 0.380

GnomAD4 genome AF: 0.496 AC: 54050 AN: 108896 Hom.: 12113 Cov.: 21 AF XY: 0.476 AC XY: 14863 AN XY: 31236

Gnomad4 AFR AF: 0.870

Gnomad4 AMR AF: 0.495

Gnomad4 ASJ AF: 0.410

Gnomad4 EAS AF: 0.322

Gnomad4 SAS AF: 0.203

Gnomad4 FIN AF: 0.329

Gnomad4 NFE AF: 0.337

Gnomad4 OTH AF: 0.462

Alfa AF: 0.405 Hom.: 7163

Bravo AF: 0.531

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 31, 2018

- -

Syndromic X-linked intellectual disability Snyder type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	1.1
Dann	Benign	0.63

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: rs3747276; hg19: chrX-21985464; COSMIC: COSV65113828;