rs1050239

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_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 (★★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

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 id is 93317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6394233-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
SMPD1	NM_000543.5 linkuse as main transcript	c.1522G>A	p.Gly508Arg	missense_variant	6/6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9 linkuse as main transcript	c.1522G>A	p.Gly508Arg	missense_variant	6/6	1	NM_000543.5	ENSP00000340409	P3	P17405-1

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

GnomAD3 exomes

AF:

0.191

AC:

48098

AN:

251326

Hom.:

4926

AF XY:

0.190

AC XY:

25790

AN XY:

135832

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 SAS exome

AF:

0.124

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

Gnomad4 AFR exome

AF:

0.133

Gnomad4 AMR exome

AF:

0.167

Gnomad4 ASJ exome

AF:

0.174

Gnomad4 EAS exome

AF:

0.139

Gnomad4 SAS exome

AF:

0.129

Gnomad4 FIN exome

AF:

0.216

Gnomad4 NFE exome

AF:

0.239

Gnomad4 OTH exome

AF:

0.204

GnomAD4 genome

AF:

0.192

AC:

29255

AN:

152074

Hom.:

2946

Cov.:

AF XY:

0.189

AC XY:

14052

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.139

Gnomad4 AMR

AF:

0.174

Gnomad4 ASJ

AF:

0.180

Gnomad4 EAS

AF:

0.146

Gnomad4 SAS

AF:

0.121

Gnomad4 FIN

AF:

0.216

Gnomad4 NFE

AF:

0.233

Gnomad4 OTH

AF:

0.189

Alfa

AF:

0.216

Hom.:

7676

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

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 27, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:4

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24977483) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 05, 2016	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. -

Niemann-Pick disease, type A

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Niemann-Pick disease, type B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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

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

MutationTaster

Benign

0.059

P;P;P;P

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

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

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