X-21977061-A-T

Variant names:

• chrX-21977061-A-T
• rs142264016
• NM_004595.5:c.330A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP7

The NM_004595.5(SMS):​c.330A>T​(p.Arg110Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R110R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: SMS NM_004595.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.00006157
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0250
• 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), Orphanet, ClinGen, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26963735).
• BP7: Synonymous conserved (PhyloP=-0.025 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMS	NM_004595.5	MANE Select	c.330A>T	p.Arg110Arg	splice_region synonymous	Exon 5 of 11	NP_004586.2
	SMS	NM_001258423.2		c.171A>T	p.Arg57Ser	missense splice_region	Exon 3 of 9	NP_001245352.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMS	ENST00000404933.7	TSL:1 MANE Select	c.330A>T	p.Arg110Arg	splice_region synonymous	Exon 5 of 11	ENSP00000385746.2
	SMS	ENST00000379404.5	TSL:3	c.171A>T	p.Arg57Ser	missense splice_region	Exon 3 of 9	ENSP00000368714.1
	SMS	ENST00000457085.2	TSL:5	c.675A>T	p.Arg225Arg	splice_region synonymous	Exon 5 of 6	ENSP00000407366.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 6

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	8.8
DANN	Uncertain	0.98
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.34	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.94	T
PhyloP100		-0.025
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.22
Sift	Benign	0.20	T
Sift4G	Benign	0.15	T
Polyphen		0.52	P
Vest4		0.32
MutPred		0.49		Gain of glycosylation at R57 (P = 0.0244)
MVP		0.80
ClinPred		0.84	D
GERP RS		0.17
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000062
dbscSNV1_RF	Benign	0.050
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: rs142264016; hg19: chrX-21995179;