rs1050239

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000543.5(SMPD1):c.1522G>A(p.Gly508Arg) variant causes a missense change. The variant allele was found at a frequency of 0.219 in 1,613,854 control chromosomes in the GnomAD database, including 40,019 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G508G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.19 ( 2946 hom., cov: 32)

Exomes 𝑓: 0.22 ( 37073 hom. )

Consequence

SMPD1
NM_000543.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 6.33

Publications

68 publications found

Variant links:

Genes affected

SMPD1 (HGNC:11120): (sphingomyelin phosphodiesterase 1) The protein encoded by this gene is a lysosomal acid sphingomyelinase that converts sphingomyelin to ceramide. The encoded protein also has phospholipase C activity. Defects in this gene are a cause of Niemann-Pick disease type A (NPA) and Niemann-Pick disease type B (NPB). Multiple transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2010]

SMPD1 Gene-Disease associations (from GenCC):

acid sphingomyelinase deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Niemann-Pick disease
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
Niemann-Pick disease type A
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
Niemann-Pick disease type B
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

SMPD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000543.5

BP4

Computational evidence support a benign effect (MetaRNN=0.0019872487).

BP6

Variant 11-6394233-G-A is Benign according to our data. Variant chr11-6394233-G-A is described in ClinVar as Benign. ClinVar VariationId is 93317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5 link	c.1522G>A	p.Gly508Arg	missense_variant	Exon 6 of 6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9 link	c.1522G>A	p.Gly508Arg	missense_variant	Exon 6 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes

AF:

0.192

AC:

29236

AN:

151956

Hom.:

2942

Cov.:

show subpopulations

Gnomad AFR

AF:

0.139

Gnomad AMI

AF:

0.299

Gnomad AMR

AF:

0.174

Gnomad ASJ

AF:

0.180

Gnomad EAS

AF:

0.147

Gnomad SAS

AF:

0.120

Gnomad FIN

AF:

0.216

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.233

Gnomad OTH

AF:

0.191

GnomAD2 exomes

AF:

0.191

AC:

48098

AN:

251326

AF XY:

0.190

show subpopulations

Gnomad AFR exome

AF:

0.135

Gnomad AMR exome

AF:

0.168

Gnomad ASJ exome

AF:

0.178

Gnomad EAS exome

AF:

0.137

Gnomad FIN exome

AF:

0.218

Gnomad NFE exome

AF:

0.230

Gnomad OTH exome

AF:

0.191

GnomAD4 exome

AF:

0.221

AC:

323546

AN:

1461780

Hom.:

37073

Cov.:

AF XY:

0.219

AC XY:

158913

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.133

AC:

4460

AN:

33476

American (AMR)

AF:

0.167

AC:

7466

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.174

AC:

4557

AN:

26136

East Asian (EAS)

AF:

0.139

AC:

5507

AN:

39696

South Asian (SAS)

AF:

0.129

AC:

11138

AN:

86250

European-Finnish (FIN)

AF:

0.216

AC:

11537

AN:

53412

Middle Eastern (MID)

AF:

0.144

AC:

828

AN:

5768

European-Non Finnish (NFE)

AF:

0.239

AC:

265705

AN:

1111928

Other (OTH)

AF:

0.204

AC:

12348

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

14924

29847

44771

59694

74618

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9012

18024

27036

36048

45060

<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:

0.192

AC:

29255

AN:

152074

Hom.:

2946

Cov.:

AF XY:

0.189

AC XY:

14052

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.139

AC:

5761

AN:

41484

American (AMR)

AF:

0.174

AC:

2659

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.180

AC:

624

AN:

3472

East Asian (EAS)

AF:

0.146

AC:

753

AN:

5162

South Asian (SAS)

AF:

0.121

AC:

583

AN:

4818

European-Finnish (FIN)

AF:

0.216

AC:

2289

AN:

10574

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.233

AC:

15870

AN:

67966

Other (OTH)

AF:

0.189

AC:

398

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1208

2417

3625

4834

6042

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

310

620

930

1240

1550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.215

Hom.:

15169

Bravo

AF:

0.187

TwinsUK

AF:

0.243

AC:

901

ALSPAC

AF:

0.241

AC:

930

ESP6500AA

AF:

0.137

AC:

604

ESP6500EA

AF:

0.229

AC:

1970

ExAC

AF:

0.192

AC:

23270

EpiCase

AF:

0.224

EpiControl

AF:

0.222

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24977483) -

Dec 15, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 05, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant Summary: The c.1522G>A in SMPD1 gene is a missense change that involves the alteration of a mildly conserved nucleotide and 3/5 in silico tools predict benign outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.19 (23261/121314 chrs tested). This frequency exceeds the maximal expected allele frequency for a pathogenic variant in this gene (0.002). A reputable database/diagnostic center has classified the variant of interest as Benign. Taking together, based on the prevalence in general population, the variant was classified as Benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Niemann-Pick disease, type A

Benign:3

May 06, 2017

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Niemann-Pick disease, type B

Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.67

T;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-1.1

PhyloP100

6.3

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.3

N;N

REVEL

Uncertain

0.50

Sift

Benign

0.16

T;T

Sift4G

Benign

0.17

T;T

Vest4

0.15

MPC

0.47

ClinPred

0.038

GERP RS

3.8

Varity_R

0.094

gMVP

0.77

Mutation Taster

=90/10

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over