X-21967253-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP2BP4_ModerateBP6_ModerateBS2

The NM_004595.5(SMS):c.107C>T(p.Ala36Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000166 in 1,205,241 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A36A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.000017 ( 0 hom. 5 hem. )

Consequence

SMS
NM_004595.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.19

Publications

1 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), PanelApp Australia, Orphanet, G2P, ClinGen

SMS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.16021037).

BP6

Variant X-21967253-C-T is Benign according to our data. Variant chrX-21967253-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2379640.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 5 XL gene

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.107C>T	p.Ala36Val	missense	Exon 2 of 11	NP_004586.2
	SMS	NM_001258423.2		c.107C>T	p.Ala36Val	missense	Exon 2 of 9	NP_001245352.1	P52788-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMS	ENST00000404933.7	TSL:1 MANE Select	c.107C>T	p.Ala36Val	missense	Exon 2 of 11	ENSP00000385746.2	P52788-1
SMS	ENST00000853889.1		c.107C>T	p.Ala36Val	missense	Exon 2 of 12	ENSP00000523948.1
SMS	ENST00000955899.1		c.107C>T	p.Ala36Val	missense	Exon 2 of 12	ENSP00000625958.1

Frequencies

GnomAD3 genomes

AF:

0.00000911

AC:

AN:

109801

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000985

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

GnomAD2 exomes

AF:

0.0000164

AC:

AN:

183248

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000109

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000173

AC:

AN:

1095394

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

360886

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26336

American (AMR)

AF:

0.000114

AC:

AN:

35184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19346

East Asian (EAS)

AF:

0.000166

AC:

AN:

30148

South Asian (SAS)

AF:

0.00

AC:

AN:

54087

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40459

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3997

European-Non Finnish (NFE)

AF:

0.0000119

AC:

AN:

839891

Other (OTH)

AF:

0.00

AC:

AN:

45946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000910

AC:

AN:

109847

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32077

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30190

American (AMR)

AF:

0.0000984

AC:

AN:

10164

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2625

East Asian (EAS)

AF:

0.00

AC:

AN:

3513

South Asian (SAS)

AF:

0.00

AC:

AN:

2534

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5706

Middle Eastern (MID)

AF:

0.00

AC:

AN:

212

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52734

Other (OTH)

AF:

0.00

AC:

AN:

1490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000494

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.026

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.77

M_CAP

Benign

0.051

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.1

PhyloP100

4.2

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.53

REVEL

Benign

0.22

Sift

Benign

0.037

Sift4G

Benign

0.20

Polyphen

0.0

Vest4

0.15

MutPred

0.38

Gain of sheet (P = 0.0043)

MVP

0.87

MPC

0.89

ClinPred

0.068

GERP RS

4.5

Varity_R

0.13

gMVP

0.29

Mutation Taster

=86/14

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over