rs1803161

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_000543.5(SMPD1):c.872G>A(p.Arg291His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,614,214 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R291R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0018 ( 2 hom. )

Consequence

SMPD1
NM_000543.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:14

Conservation

PhyloP100: 7.59

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 Likely_benign. Variant got -4 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000543.5

BP4

Computational evidence support a benign effect (MetaRNN=0.14118597).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5 linkuse as main transcript	c.872G>A	p.Arg291His	missense_variant	2/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9 linkuse as main transcript	c.872G>A	p.Arg291His	missense_variant	2/6	1	NM_000543.5	P3	P17405-1

Frequencies

GnomAD3 genomes

AF:

0.00140

AC:

213

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00268

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00110

AC:

276

AN:

251420

Hom.:

AF XY:

0.00110

AC XY:

149

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00215

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.00183

AC:

2671

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00180

AC XY:

1307

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00231

Gnomad4 OTH exome

AF:

0.00101

GnomAD4 genome

AF:

0.00140

AC:

213

AN:

152324

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000649

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00268

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00218

Hom.:

Bravo

AF:

0.00126

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00114

AC:

138

EpiCase

AF:

0.00158

EpiControl

AF:

0.00148

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in patients with Niemann-Pick type B who had significant residual enzyme activity, who were also heterozygous for a second variant in SMPD1; the phase of these variants was not reported (Simonaro et al., 2002; Pavlu-Pereira et al., 2005; Zampieri et al., 2016; Lipinski et al., 2019); This variant is associated with the following publications: (PMID: 30795770, 26499107, 26981555, 29140481, 30788890, 15877209, 28590786, 20111001, 12369017) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 20, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 28, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SMPD1 p.Arg291His variant was identified in 4 of 558 proband chromosomes (frequency: 0.0072) from individuals or families with Niemann-Pick Disease type B (Simonaro_2002_PMID:12369017; Pavlâ‰ˆÃ˜-Pereira_2005_PMID:15877209; Reunert_2015_PMID:26981555; Zampieri_2016_PMID:26499107). The variant was identified in dbSNP (ID: rs1803161) and ClinVar (classified as uncertain significance by Invitae, EGL Genetics, Fulgent Genetics, Integrated Genetics and Mayo Clinic Genetic Testing). The variant was identified in control databases in 325 of 282810 chromosomes at a frequency of 0.001149 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 288 of 129142 chromosomes (freq: 0.00223), Other in 7 of 7224 chromosomes (freq: 0.000969), African in 19 of 24968 chromosomes (freq: 0.000761), European (Finnish) in 5 of 25108 chromosomes (freq: 0.000199), Latino in 5 of 35434 chromosomes (freq: 0.000141) and Ashkenazi Jewish in 1 of 10366 chromosomes (freq: 0.000096), but was not observed in the East Asian or South Asian populations. The p.Arg291 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Sep 25, 2023	PS3_Supporting, PM3_Supporting, PP1, PP3 -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 21, 2018	- -

Niemann-Pick disease, type A

Pathogenic:1Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 03, 2020	- -
Pathogenic, flagged submission	clinical testing	Baylor Genetics	-	- -
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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

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

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 06, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 291 of the SMPD1 protein (p.Arg291His). This variant is present in population databases (rs1803161, gnomAD 0.2%). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 12369017, 26499107, 30795770). This variant is also known as R289H. ClinVar contains an entry for this variant (Variation ID: 195085). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 07, 2023

Variant summary: SMPD1 c.872G>A (p.Arg291His) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 251420 control chromosomes, predominantly at a frequency of 0.0022 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is similar to the expected frequency for a pathogenic variant in SMPD1 causing Niemann-Pick disease type B (0.0022 vs 0.0022), allowing no conclusion about variant significance. c.872G>A has been reported in the literature in individuals affected with Niemann-Pick disease type B and Parkinsons disease (Alcalay_2019, Kirkegaard_2010, Pavlu-Pereira_2005, Reunert_2016, Simonaro_2002, Zampieri_2015, Lipinski_2019). Due to the relatively high frequency of this variant in controls, interpretation of its presence in patients is unclear. Fibroblasts from patients with this variant along with a pathogenic variant had ASM enzyme activity which varied between 10-50% of wild-type (Pavlu-Pereira_2005, Kirkegaard_2010), however the variant was not tested in isolation. The following publications have been ascertained in the context of this evaluation (PMID: 30788890, 28590786, 20111001, 30795770, 15877209, 26981555, 12369017, 26499107). All the 11 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2021

The c.872G>A (p.R291H) alteration is located in exon 2 (coding exon 2) of the SMPD1 gene. This alteration results from a G to A substitution at nucleotide position 872, causing the arginine (R) at amino acid position 291 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

SMPD1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 01, 2023

The SMPD1 c.872G>A variant is predicted to result in the amino acid substitution p.Arg291His. This variant has been documented in the compound heterozygous state in at least two individuals thought to have Niemann-Pick disease; however in one case the second variant is of uncertain significance (Zampieri et al. 2016. PubMed ID: 26499107) and in the additional case(s) full genotype information was not provided (Simonaro et al. 2002. PubMed ID: 12369017, reported as R289H). This variant along with a second missense variant in this gene was also reported in one boy with Niemann-Pick disease, he also carried a homozygous 24bp duplication in CHIT1 gene (Reported as p.Arg289His in Table 1, Lipiński. 2019. PubMed ID: 30795770). This variant was also reported in one individual with Parkinson’s disease (Table S3, Robak. 2017. PubMed ID: 29140481). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Sphingomyelin/cholesterol lipidosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

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

Jan 22, 2020

The p.Arg291His variant in SMPD1 (also known as p.Arg289His due to a difference in cDNA numbering) has been reported in at least 5 individuals with Niemann-Pick disease (PMID: 29555840, 15877209, 12369017, 12369017, 20111001, 30795770) and has been identified in 0.223% (288/129142) of European (non-Finnish) chromosomes, 0.076% (19/24968) of African chromosomes, and 0.020% (5/25108) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1803161). 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 at least 1 affected homozygote and in combination with reported pathogenic or likely pathogenic variants in 2 individuals with Niemann-Pick disease increases the likelihood that the p.Arg291His variant is pathogenic (VariationID: 2994, 550112; PMID: 29555840, 20111001, 15877209). In summary, the clinical significance of the p.Arg291His variant is uncertain. ACMG/AMP Criteria applied: BS1, PM3, PP3 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.051

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

.;D;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.30

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.4

D;D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Vest4

0.87

MVP

0.99

MPC

0.89

ClinPred

0.087

GERP RS

4.9

Varity_R

0.75

gMVP

0.86

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