rs144873307

Positions:

chr11-6394029-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000543.5(SMPD1):c.1474G>A(p.Gly492Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,614,158 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 1 hom. )

Consequence

SMPD1
NM_000543.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:16B:1

Conservation

PhyloP100: 0.00900

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:

SMPD1 (HGNC:):

SMPD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.025081277).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMPD1	NM_000543.5 linkuse as main transcript	c.1474G>A	p.Gly492Ser	missense_variant	5/6	ENST00000342245.9	NP_000534.3	P17405-1Q59EN6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9 linkuse as main transcript	c.1474G>A	p.Gly492Ser	missense_variant	5/6	1	NM_000543.5	ENSP00000340409.4		P17405-1

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

177

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000580

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00187

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000935

AC:

235

AN:

251424

Hom.:

AF XY:

0.000979

AC XY:

133

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.000947

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00155

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.00184

AC:

2695

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00179

AC XY:

1305

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000893

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.00222

Gnomad4 OTH exome

AF:

0.00141

GnomAD4 genome

AF:

0.00117

AC:

178

AN:

152268

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000578

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00187

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00159

Hom.:

Bravo

AF:

0.00102

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000955

AC:

116

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00245

EpiControl

AF:

0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:16Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	SMPD1: BP4 -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 18, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 12, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2022	Reported in a patient with Parkinson disease in published literature; however, additional segregation information was not provided (Alcalay et al., 2019); Reported in the heterozygous state in a patient with a suspected lysosomal storage disease in published literature; however, the patient also harbored variants in other genes (Wang et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23252888, 28703315, 30788890, 26499107, 25933391, 34426522) -

Niemann-Pick disease, type A

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Baylor Genetics	May 05, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Niemann-Pick disease, type B

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Sphingomyelin/cholesterol lipidosis

Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Gly493Ser variant in SMPD1 (also known as p.Gly491Ser due to a difference in cDNA numbering) has been reported in at least 2 individuals with Niemann-Pick disease (PMID: 23252888) and has been identified in 0.152% (196/129134) of European (non-Finnish) chromosomes, 0.095% (29/30616) of South Asian chromosomes, and 0.052% (13/24950) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs144873307). This variant has also been reported in ClinVar (VariationID: 445832) as a VUS by Children's Mercy Hospital and Clinics, EGL Genetic Diagnostics, Integrated Genetics, and Mayo Clinic Genetic Testing Laboratories. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The presence of this variant in combination with a reported likely pathogenic variant and in 2 individuals with Niemann-Pick disease increases the likelihood that the p.Gly492Ser variant is pathogenic (VariationID: 100731; PMID: 23252888). The phenotype of individuals compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being less than 10% of normal, consistent with disease (PMID: 23252888). In summary, the clinical significance of the p.Gly492Ser variant is uncertain. ACMG/AMP Criteria applied: BS1, BP4, PM3, PP4 (Richards 2015). -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 03, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 06, 2024

Variant summary: SMPD1 c.1474G>A (p.Gly492Ser) results in a non-conservative amino acid change located in the Sphingomyelin phosphodiesterase, C-terminal domain (IPR045473) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00093 in 251524 control chromosomes, predominantly at a frequency of 0.0015 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in SMPD1 causing Niemann-Pick Disease Type B (0.00093 vs 0.0022), allowing no conclusion about variant significance. c.1474G>A has been reported in the literature as a biallelic genotype in compound heterozygosity with a different pathogenic variant (c.739G>A, p.Gly247Ser) in two individuals, one of whom was reportedly asymptomatic and the other affected with Niemann-Pick Disease Type B (example, Irun_2013). These data do not allow unequivocal conclusions about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function in-vitro, however, due to the compound heterozygous genotype, does not allow convincing conclusions about the variant effect in isolation (Irun_2013). The following publications have been ascertained in the context of this evaluation (PMID: 25933391, 23252888, 28703315, 26499107). ClinVar contains an entry for this variant (Variation ID: 445832). Based on the evidence outlined above, the variant was classified as uncertain significance. -

SMPD1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2024

The SMPD1 c.1474G>A variant is predicted to result in the amino acid substitution p.Gly492Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.15% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2021

(Irun, 2013) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 16, 2022

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 492 of the SMPD1 protein (p.Gly492Ser). This variant is present in population databases (rs144873307, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with Niemann-Pick disease type B (PMID: 23252888). ClinVar contains an entry for this variant (Variation ID: 445832). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SMPD1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.27

CADD

Benign

7.3

DANN

Benign

0.80

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.79

T;T

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.025

T;T

MetaSVM

Benign

-0.89

PrimateAI

Benign

0.30

PROVEAN

Benign

0.050

N;N

REVEL

Benign

0.25

Sift

Benign

0.42

T;T

Sift4G

Benign

0.50

T;T

Vest4

0.26

MVP

0.80

MPC

0.21

ClinPred

0.0013

GERP RS

-6.9

Varity_R

0.070

gMVP

0.51

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