X-21967253-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

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 id is 2379640.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SMS	NM_004595.5 linkuse as main transcript	c.107C>T	p.Ala36Val	missense_variant	2/11	ENST00000404933.7
SMS	NM_001258423.2 linkuse as main transcript	c.107C>T	p.Ala36Val	missense_variant	2/9
SMS	XM_005274582.3 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	2/11
SMS	XM_011545568.3 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMS	ENST00000404933.7 linkuse as main transcript	c.107C>T	p.Ala36Val	missense_variant	2/11	1	NM_004595.5	P1	P52788-1
SMS	ENST00000457085.2 linkuse as main transcript	c.452C>T	p.Ala151Val	missense_variant	2/6	5
SMS	ENST00000379404.5 linkuse as main transcript	c.107C>T	p.Ala36Val	missense_variant	2/9	3			P52788-2
SMS	ENST00000478094.1 linkuse as main transcript	n.154C>T		non_coding_transcript_exon_variant	2/5	4

Frequencies

GnomAD3 genomes

AF:

0.00000911

AC:

AN:

109801

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32021

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

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

183248

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

67708

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000166

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000910

AC:

AN:

109847

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32077

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000984

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.32

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.026

T;.

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.051

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.1

L;L

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.53

N;N

REVEL

Benign

0.22

Sift

Benign

0.037

D;D

Sift4G

Benign

0.20

T;T

Polyphen

0.0

B;B

Vest4

0.15

MutPred

0.38

Gain of sheet (P = 0.0043);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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over