rs769904764

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000543.5(SMPD1):c.1492C>T(p.Arg498Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R498H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

SMPD1
NM_000543.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 5.60

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 Pathogenic. Variant got 20 ACMG points.

PS1

Transcript NM_000543.5 (SMPD1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000543.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-6394204-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 167712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 11-6394203-C-T is Pathogenic according to our data. Variant chr11-6394203-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 198095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6394203-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5 linkuse as main transcript	c.1492C>T	p.Arg498Cys	missense_variant	6/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9 linkuse as main transcript	c.1492C>T	p.Arg498Cys	missense_variant	6/6	1	NM_000543.5	P3	P17405-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

251044

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000574

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type A

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 09, 2018	- -
Likely pathogenic, criteria provided, single submitter	research	Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS	Apr 25, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 05, 2023	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 11, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 26, 2014	- -

SMPD1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 23, 2023

The SMPD1 c.1492C>T variant is predicted to result in the amino acid substitution p.Arg498Cys. This variant has been reported in individuals with Niemann-Pick disease (reported as R496L in Simonaro et al. 2002. PubMed ID: 12369017; Zhang et al. 2013. PubMed ID: 23356216; Hu et al. 2021. PubMed ID: 33675270). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-6415433-C-T). This variant is interpreted as likely pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 16, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 498 of the SMPD1 protein (p.Arg498Cys). This variant is present in population databases (rs769904764, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of Niemann-Pick disease (PMID: 12369017, 23356216; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 198095). 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 expected to disrupt SMPD1 protein function. This variant disrupts the p.Arg498 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1391960, 1885770, 2023926, 18815062). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Sphingomyelin/cholesterol lipidosis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 22, 2020

The p.Arg498Cys variant in SMPD1 (also known as p.Arg496Cys due to a difference in cDNA numbering) has been reported in at least 3 individuals with Niemann-Pick disease (PMID: 17011332, 25834946, 23356216) and has been identified in 0.003% (1/30612) of South Asian chromosomes and 0.002% (3/128792) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs769904764). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 198095) as likely pathogenic by EGL Genetic Diagnostics, Counsyl, and Invitae. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with reported pathogenic variants in 2 individuals with Niemann-Pick disease increases the likelihood that the p.Arg498Cys variant is pathogenic (VariationID: 198095, 25834946; PMID: 17011332, 25834946). The phenotype of an individual homozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal, consistent with disease (PMID: 23356216). Multiple variants in the same region as p.Arg498Cys have been reported in association with disease in ClinVar and the literature and the variant is located in a region of SMPD1 that is essential to protein folding and stability, suggesting that this variant is in a hot spot and functional domain and supports pathogenicity (VariationID: 2991, 198095; PMID: 18815062, 27725636; DOI: 10.1111/febs.13655). Two additional pathogenic and likely pathogenic variants, resulting in a different amino acid change at the same position, p.Arg498Leu and p.Arg498His, have been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (VariationID: 2980, 167712; PMID: 29995201, 18815062, 15221801, 27338287, 26499107, 27725636). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PM1, PM3, PP3, PP4 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.57

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-7.2

D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.97

MVP

0.99

MPC

0.93

ClinPred

1.0

GERP RS

3.8

Varity_R

0.88

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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