NM_004595.5:c.170+30C>T

Variant names:

• chrX-21967346-C-T
• rs3747276
• NM_004595.5:c.170+30C>T

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: -0.133
• Publications: 8 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 -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 VariationId 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 rank	MANE	Protein	UniProt
SMS	NM_004595.5	c.170+30C>T		intron_variant	Intron 2 of 10	ENST00000404933.7	NP_004586.2
SMS	NM_001258423.2	c.170+30C>T		intron_variant	Intron 2 of 8		NP_001245352.1
SMS	XM_005274582.3	c.68+30C>T		intron_variant	Intron 2 of 10		XP_005274639.1
SMS	XM_011545568.3	c.68+30C>T		intron_variant	Intron 2 of 10		XP_011543870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMS	ENST00000404933.7	c.170+30C>T		intron_variant	Intron 2 of 10	1	NM_004595.5	ENSP00000385746.2
SMS	ENST00000457085.2	c.515+30C>T		intron_variant	Intron 2 of 5	5		ENSP00000407366.2
SMS	ENST00000379404.5	c.170+30C>T		intron_variant	Intron 2 of 8	3		ENSP00000368714.1
SMS	ENST00000478094.1	n.217+30C>T		intron_variant	Intron 2 of 4	4

Frequencies

GnomAD3 genomes AF: 0.496 AC: 53980 AN: 108844 Hom.: 12101 Cov.: 21

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

GnomAD2 exomes AF: 0.386 AC: 70063 AN: 181683 AF XY: 0.354

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 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

African (AFR) AF: 0.888 AC: 23324 AN: 26260

American (AMR) AF: 0.467 AC: 16385 AN: 35049

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 7868 AN: 19189

East Asian (EAS) AF: 0.312 AC: 9347 AN: 29983

South Asian (SAS) AF: 0.219 AC: 11830 AN: 53973

European-Finnish (FIN) AF: 0.357 AC: 14353 AN: 40189

Middle Eastern (MID) AF: 0.366 AC: 1502 AN: 4104

European-Non Finnish (NFE) AF: 0.340 AC: 284013 AN: 836421

Other (OTH) AF: 0.380 AC: 17377 AN: 45750

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

African (AFR) AF: 0.870 AC: 25879 AN: 29757

American (AMR) AF: 0.495 AC: 4978 AN: 10066

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 1071 AN: 2613

East Asian (EAS) AF: 0.322 AC: 1105 AN: 3436

South Asian (SAS) AF: 0.203 AC: 522 AN: 2570

European-Finnish (FIN) AF: 0.329 AC: 1835 AN: 5577

Middle Eastern (MID) AF: 0.376 AC: 80 AN: 213

European-Non Finnish (NFE) AF: 0.337 AC: 17708 AN: 52529

Other (OTH) AF: 0.462 AC: 678 AN: 1469

Alfa AF: 0.405 Hom.: 7163

Bravo AF: 0.531

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 31, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Syndromic X-linked intellectual disability Snyder type Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: 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	-0.97
CADD	Benign	1.1
DANN	Benign	0.63
PhyloP100		-0.13
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: rs3747276; hg19: chrX-21985464; COSMIC: COSV65113828;