X-21967232-T-C

Variant names:

• chrX-21967232-T-C
• NM_004595.5:c.86T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004595.5(SMS):​c.86T>C​(p.Ile29Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 21)
• Consequence: SMS NM_004595.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.95

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMS	NM_004595.5	c.86T>C	p.Ile29Thr	missense_variant	Exon 2 of 11	ENST00000404933.7	NP_004586.2
SMS	NM_001258423.2	c.86T>C	p.Ile29Thr	missense_variant	Exon 2 of 9		NP_001245352.1
SMS	XM_005274582.3	c.-17T>C		5_prime_UTR_variant	Exon 2 of 11		XP_005274639.1
SMS	XM_011545568.3	c.-17T>C		5_prime_UTR_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.86T>C	p.Ile29Thr	missense_variant	Exon 2 of 11	1	NM_004595.5	ENSP00000385746.2
SMS	ENST00000457085.2	c.431T>C	p.Ile144Thr	missense_variant	Exon 2 of 6	5		ENSP00000407366.2
SMS	ENST00000379404.5	c.86T>C	p.Ile29Thr	missense_variant	Exon 2 of 9	3		ENSP00000368714.1
SMS	ENST00000478094.1	n.133T>C		non_coding_transcript_exon_variant	Exon 2 of 5	4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.86T>C (p.I29T) alteration is located in exon 2 (coding exon 2) of the SMS gene. This alteration results from a T to C substitution at nucleotide position 86, causing the isoleucine (I) at amino acid position 29 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.056	T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.60
Sift	Uncertain	0.0070	D;D
Sift4G	Benign	0.077	T;D
Polyphen		0.096	B;P
Vest4		0.61
MutPred		0.61		Loss of stability (P = 0.0025);Loss of stability (P = 0.0025);
MVP		0.79
MPC		1.2
ClinPred		0.82	D
GERP RS		5.3
Varity_R		0.58
gMVP		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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-21985350;