X-21977180-T-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong

The NM_004595.5(SMS):c.449T>C(p.Ile150Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

SMS
NM_004595.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.64

Publications

13 publications found

Variant links:

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

SMS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 19 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 2.3162 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to syndromic X-linked intellectual disability Snyder type.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMS	NM_004595.5 link	c.449T>C	p.Ile150Thr	missense_variant	Exon 5 of 11	ENST00000404933.7	NP_004586.2	P52788-1
SMS	NM_001258423.2 link	c.290T>C	p.Ile97Thr	missense_variant	Exon 3 of 9		NP_001245352.1	P52788-2
SMS	XM_005274582.3 link	c.347T>C	p.Ile116Thr	missense_variant	Exon 5 of 11		XP_005274639.1
SMS	XM_011545568.3 link	c.347T>C	p.Ile116Thr	missense_variant	Exon 5 of 11		XP_011543870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMS	ENST00000404933.7 link	c.449T>C	p.Ile150Thr	missense_variant	Exon 5 of 11	1	NM_004595.5	ENSP00000385746.2	P52788-1
SMS	ENST00000457085.2 link	c.794T>C	p.Ile265Thr	missense_variant	Exon 5 of 6	5		ENSP00000407366.2	H7C2R7
SMS	ENST00000379404.5 link	c.290T>C	p.Ile97Thr	missense_variant	Exon 3 of 9	3		ENSP00000368714.1	P52788-2
SMS	ENST00000478094.1 link	n.402T>C		non_coding_transcript_exon_variant	Exon 4 of 5	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.14e-7

AC:

AN:

1093941

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

359375

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26315

American (AMR)

AF:

0.00

AC:

AN:

35201

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19363

East Asian (EAS)

AF:

0.00

AC:

AN:

30195

South Asian (SAS)

AF:

0.00

AC:

AN:

54038

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4123

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

838213

Other (OTH)

AF:

0.00

AC:

AN:

45961

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.53

MutationAssessor

Pathogenic

3.6

H;.

PhyloP100

7.6

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.9

D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.028

D;D

Polyphen

1.0

D;P

Vest4

0.96

MutPred

0.84

Loss of stability (P = 0.0103);.;

MVP

0.99

MPC

2.2

ClinPred

0.99

GERP RS

5.7

Varity_R

0.92

gMVP

0.99

Mutation Taster

=4/96

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over