chr11-6394029-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G492R) has been classified as Uncertain significance.
Frequency
Consequence
NM_000543.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMPD1 | NM_000543.5 | c.1474G>A | p.Gly492Ser | missense_variant | 5/6 | ENST00000342245.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMPD1 | ENST00000342245.9 | c.1474G>A | p.Gly492Ser | missense_variant | 5/6 | 1 | NM_000543.5 | P3 |
Frequencies
GnomAD3 genomes AF: 0.00116 AC: 177AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000935 AC: 235AN: 251424Hom.: 0 AF XY: 0.000979 AC XY: 133AN XY: 135906
GnomAD4 exome AF: 0.00184 AC: 2695AN: 1461890Hom.: 1 Cov.: 32 AF XY: 0.00179 AC XY: 1305AN XY: 727248
GnomAD4 genome AF: 0.00117 AC: 178AN: 152268Hom.: 0 Cov.: 32 AF XY: 0.00117 AC XY: 87AN XY: 74440
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jun 12, 2017 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 18, 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, 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. - |
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 | - - |
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 | Mar 08, 2018 | Variant summary: SMPD1 c.1474G>A (p.Gly492Ser) results in a non-conservative amino acid change located in the metallophosphatase domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. This frequency is not significantly higher than expected for a pathogenic variant in SMPD1 causing Niemann-Pick Disease (0.00094 vs 0.0022), allowing no conclusion about variant significance. c.1474G>A has been reported in the literature in individuals affected with Niemann-Pick Disease. These data indicate that the variant may be associated with disease, however additional segregation studies are needed to classify the variant with confidence. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-Possibly Pathogenic. - |
SMPD1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 15, 2023 | 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 | Invitae | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at