rs142215226

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000543.5(SMPD1):c.340G>A(p.Val114Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000668 in 1,612,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00069 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00067 ( 0 hom. )

Consequence

SMPD1
NM_000543.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:19

Conservation

PhyloP100: 2.92

Publications

8 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.025103807).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5 link	c.340G>A	p.Val114Met	missense_variant	Exon 2 of 6	ENST00000342245.9	NP_000534.3	P17405-1Q59EN6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9 link	c.340G>A	p.Val114Met	missense_variant	Exon 2 of 6	1	NM_000543.5	ENSP00000340409.4		P17405-1

Frequencies

GnomAD3 genomes

AF:

0.000690

AC:

105

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.000751

AC:

188

AN:

250390

AF XY:

0.000753

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00107

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.000666

AC:

972

AN:

1460468

Hom.:

Cov.:

AF XY:

0.000694

AC XY:

504

AN XY:

726546

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33426

American (AMR)

AF:

0.000403

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00241

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.000325

AC:

AN:

86188

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00318

AC:

AN:

4718

European-Non Finnish (NFE)

AF:

0.000691

AC:

768

AN:

1111944

Other (OTH)

AF:

0.00116

AC:

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

121

182

242

303

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000689

AC:

105

AN:

152294

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41568

American (AMR)

AF:

0.000850

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

68030

Other (OTH)

AF:

0.00237

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000885

Hom.:

Bravo

AF:

0.000778

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000931

AC:

ExAC

AF:

0.000758

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00142

EpiControl

AF:

0.00124

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:8

Aug 31, 2016

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 25, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 22, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3_Moderate -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 16, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SMPD1 p.Val113Met variant was identified in the literature in one homozygote patient of six patients with hyperprolinaemia (freq: 0.167) (Reid_2017_PMID:28255779). A case study of two siblings with Niemann-Pick Disease type B also identified the V113M variant along with a H554Y variant in the SMPD1 gene; the mother carried the V113M variant and the father carried the H554Y variant (Gucev_2013_PMID:22367733). The variant was also identified in dbSNP (ID: rs142215226), ClinVar (classified as a VUS by EGL Genetics, Praxis fuer Humangenetik Tuebingen and Genomic Research Center, Shahid Beheshti University of Medical Sciences), Cosmic (FATHMM predicted pathogenic; score=0.72) and LOVD 3.0. The variant was identified in control databases in 207 of 281774 chromosomes at a frequency of 0.000735 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 32 of 10360 chromosomes (freq: 0.003089), Other in 10 of 7204 chromosomes (freq: 0.001388), European (non-Finnish) in 136 of 128262 chromosomes (freq: 0.00106), South Asian in 12 of 30614 chromosomes (freq: 0.000392), Latino in 13 of 35426 chromosomes (freq: 0.000367) and African in 4 of 24908 chromosomes (freq: 0.000161), while the variant was not observed in the East Asian and European (Finnish) populations. The p.Val113 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. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 21, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2 -

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

Uncertain:4

Aug 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 114 of the SMPD1 protein (p.Val114Met). This variant is present in population databases (rs142215226, gnomAD 0.3%). This missense change has been observed in individual(s) with Niemann-Pick disease type B (PMID: 22367733). It has also been observed to segregate with disease in related individuals. This variant is also known as V112M. ClinVar contains an entry for this variant (Variation ID: 281705). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Oct 01, 2021

Myriad Genetics, Inc.

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_000543.4(SMPD1):c.340G>A(V114M) is a missense variant classified as a variant of uncertain significance in the context of Niemann-Pick disease, SMPD1-related. V114M has been observed in cases with relevant disease (PMID: 22367733). Functional assessments of this variant are not available in the literature. V114M has been observed in population frequency databases (gnomAD: ASJ 0.31%). In summary, there is insufficient evidence to classify NM_000543.4(SMPD1):c.340G>A(V114M) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Jun 04, 2020

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sphingomyelin/cholesterol lipidosis

Uncertain:2

Aug 02, 2019

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 22, 2020

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Val114Met variant in SMPD1 (also known as p.Val112Met due to a difference in cDNA numbering) has been reported in at least 2 Macedonian individuals with Niemann-Pick Disease, segregated with disease in 2 affected relatives from 1 family (PMID: 22367733), and has been identified in 0.309% (32/10360) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142215226). This variant has also been reported in ClinVar (VariationID: 281705) as a VUS by EGL Genetic Diagnostics, CeGaT Praxis fuer Humangenetik Tuebingen, Shahid Beheshti University of Medical Sciences, and Illumina Clinical Services Laboratory. The Val at position 114 is not highly conserved in mammals and evolutionary distant species, and 1 mammal (Ferret) carries a Met, raising the supporting that this change at this position may be tolerated. Additional computational prediction tools do not provide strong support for or against an impact to the protein. The p.Val114Met variant is located in a region of SMPD1 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 30788890). The phenotype of an individual compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomelinase activity being less than 10% of normal consistent with disease (PMID: 22367733). In summary, the clinical significance of the p.Val114Met variant is uncertain. ACMG/AMP Criteria applied: BS1, PP4, PM3_supporting, PM1_supporting (Richards 2015). -

Niemann-Pick disease, type A

Uncertain:2

May 18, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 18, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Mar 14, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SMPD1 c.340G>A (p.Val114Met) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00075 in 250390 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SMPD1 causing Niemann-Pick Disease (0.00075 vs 0.0022), allowing no conclusion about variant significance. c.340G>A has been reported in the compound heterozygous state and an unknown state in the literature in individuals affected with Niemann-Pick Disease (example, Gucev_2013, Sheth_2024), however at least 1 of these studies did not have strong evidence for causality (Sheth_2024). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity (example, Chew_2023). The following publications have been ascertained in the context of this evaluation (PMID: 22367733, 31941852, 39572736, 38730490). ClinVar contains an entry for this variant (Variation ID: 281705). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

SMPD1-related disorder

Uncertain:1

Sep 04, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SMPD1 c.340G>A variant is predicted to result in the amino acid substitution p.Val114Met. This variant was reported in the compound heterozygous state in two siblings with Niemann-Pick Disease type B (Gucev et al. 2013. PubMed ID: 22367733). This variant was also reported in the homozygous state in an individual with hyperprolinaemia in which causative variants in SLC25A22 were detected (Reid et al. 2017. PubMed ID: 28255779). In this homozygous patient, leucocyte sphingomyelinase activity was 0.43 which was within normal limits, indicating this variant is less likely to be pathogenic (Reid et al. 2017. PubMed ID: 28255779). This variant was also reported in 3 patients with Parkinson's disease from a large cohort study (Alcalay et al. 2019. PubMed ID: 30788890). This variant is reported in 0.31% of alleles in individuals of Ashkenazi Jewish 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

May 09, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.340G>A (p.V114M) 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 340, causing the valine (V) at amino acid position 114 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.026

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.73

T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.025

T;T

MetaSVM

Uncertain

0.63

PhyloP100

2.9

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.2

N;N

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0030

D;T

Sift4G

Uncertain

0.010

D;T

Vest4

0.32

MVP

0.96

MPC

0.30

ClinPred

0.059

GERP RS

3.2

PromoterAI

0.0046

Neutral

(source)

Varity_R

0.23

gMVP

0.84

Mutation Taster

=7/93

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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rs142215226

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