rs142215226
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_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
NM_000543.5 missense
Scores
2
6
9
Clinical Significance
Conservation
PhyloP100: 2.92
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM1
In a disulfide_bond (size 76) in uniprot entity ASM_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_000543.5
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.025103807).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMPD1 | NM_000543.5 | c.340G>A | p.Val114Met | missense_variant | 2/6 | ENST00000342245.9 | NP_000534.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMPD1 | ENST00000342245.9 | c.340G>A | p.Val114Met | missense_variant | 2/6 | 1 | NM_000543.5 | ENSP00000340409 | P3 |
Frequencies
GnomAD3 genomes AF: 0.000690 AC: 105AN: 152176Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000751 AC: 188AN: 250390Hom.: 0 AF XY: 0.000753 AC XY: 102AN XY: 135464
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GnomAD4 exome AF: 0.000666 AC: 972AN: 1460468Hom.: 0 Cov.: 34 AF XY: 0.000694 AC XY: 504AN XY: 726546
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GnomAD4 genome AF: 0.000689 AC: 105AN: 152294Hom.: 0 Cov.: 33 AF XY: 0.000645 AC XY: 48AN XY: 74460
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:20
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:8
Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 25, 2018 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 16, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Sep 22, 2023 | PS3_Moderate - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 21, 2023 | PM2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 31, 2016 | - - |
Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Jun 04, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 03, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 23, 2022 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 01, 2021 | 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. - |
Niemann-Pick disease, type A Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 22, 2023 | The SMPD1 c.340G>A (p.Val114Met) variant is a missense variant. This variant has been reported in one study, in which it is found in a compound heterozygous state with another missense variant in two siblings affected with acid sphingomyelinase deficiency (PMID: 22367733). The c.340G>A variant is reported at a frequency of 0.003089 in the Ashkenazi Jewish population of the Genome Aggregation Database (version 2.1.1). This variant is located in the saposin B-like domain of SMPD1 (PMID: 27725636). Based on the available evidence, the c.340G>A (p.Val114Met) variant is classified as a variant of uncertain significance for Niemann-Pick disease, type A. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 18, 2017 | - - |
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.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). - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 02, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 20, 2024 | Variant summary: SMPD1 c.340G>A (p.Val114Met) results in a conservative amino acid change located in the Saposin B type domain (IPR008139) of 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 literature as a compound heterozygous genotype in at-least two individuals (siblings) from a family affected with an early onset form of Niemann-Pick Disease Type B (example, Gucev_2013 cited in Ota_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22367733, 31941852). ClinVar contains an entry for this variant (Variation ID: 281705). 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 | May 09, 2022 | 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. - |
SMPD1-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 04, 2024 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Uncertain
D;T
Sift4G
Uncertain
D;T
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at