chrX-21940866-C-T

Variant names:

• chrX-21940866-C-T
• rs1424492466
• NM_004595.5:c.42C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_004595.5(SMS):​c.42C>T​(p.Gly14Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 109,669 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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 0.000027 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SMS NM_004595.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.271
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant X-21940866-C-T is Benign according to our data. Variant chrX-21940866-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1739528.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.271 with no splicing effect.

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.42C>T	p.Gly14Gly	synonymous	Exon 1 of 11	NP_004586.2
	SMS	NM_001258423.2		c.42C>T	p.Gly14Gly	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.42C>T	p.Gly14Gly	synonymous	Exon 1 of 11	ENSP00000385746.2	P52788-1
	SMS	ENST00000853889.1		c.42C>T	p.Gly14Gly	synonymous	Exon 1 of 12	ENSP00000523948.1
	SMS	ENST00000955899.1		c.42C>T	p.Gly14Gly	synonymous	Exon 1 of 12	ENSP00000625958.1

Frequencies

GnomAD3 genomes AF: 0.0000274 AC: 3 AN: 109669 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000982

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

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 988302 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 314550

African (AFR) AF: 0.00 AC: 0 AN: 20748

American (AMR) AF: 0.00 AC: 0 AN: 23276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16738

East Asian (EAS) AF: 0.00 AC: 0 AN: 21843

South Asian (SAS) AF: 0.00 AC: 0 AN: 46006

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2654

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 791050

Other (OTH) AF: 0.00 AC: 0 AN: 41183

GnomAD4 genome AF: 0.0000274 AC: 3 AN: 109669 Hom.: 0 Cov.: 22 AF XY: 0.0000307 AC XY: 1 AN XY: 32521

African (AFR) AF: 0.0000982 AC: 3 AN: 30542

American (AMR) AF: 0.00 AC: 0 AN: 10599

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2594

East Asian (EAS) AF: 0.00 AC: 0 AN: 3421

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5597

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 51843

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	SMS-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Uncertain	0.98
PhyloP100		0.27
PromoterAI		-0.097	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: rs1424492466; hg19: chrX-21958984;