rs398123478
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000543.5(SMPD1):c.1624C>T(p.Arg542*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000229 in 1,614,218 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 Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000024 ( 0 hom. )
Consequence
SMPD1
NM_000543.5 stop_gained
NM_000543.5 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 3.67
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 Pathogenic. Variant got 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-6394335-C-T is Pathogenic according to our data. Variant chr11-6394335-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 93318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6394335-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152210Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251346Hom.: 0 AF XY: 0.0000884 AC XY: 12AN XY: 135812
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GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461890Hom.: 0 Cov.: 34 AF XY: 0.0000358 AC XY: 26AN XY: 727246
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GnomAD4 genome 0.0000131 AC: 2AN: 152328Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2AN XY: 74488
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Niemann-Pick disease, type A Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Jun 02, 2023 | The observed stop gained variant c.1624C>T(p.Arg542Ter) in the SMPD1 gene has been reported previously in multiple individuals affected with Niemann-Pick disease. In this study the p. (Arg542*) (c.1624C>T) mutation was the most commonly identified mutation, found in 22% (26 out of 120) of the alleles tested, but haplotype analysis for this mutation did not identify a founder effect for the Indian population (Ranganath P, et al., 2016). Though this variant is present in the last exon, there are other pathogenic variants reported beyond this position in the ClinVar database. This variant is reported with the allele frequency 0.01% in the gnomAD Exomes. It is submitted to ClinVar as Pathogenic/Likely pathogenic. Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Apr 24, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Oct 27, 2023 | A homozygous variation in exon 6 of the SMPD1 gene that results in a premature truncation of the protein at codon 542 was detected. The observed variant c.1624C>T(p.Arg542Ter) has not been reported in the 1000 genomes and has a MAF of 0.006% in gnomAD database. The in silico prediction of the variant is disease causing by DANN and MutationTaster. In summary, the variant meets our criteria to be classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 29, 2019 | Variant summary: SMPD1 c.1624C>T (p.Arg542X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.4e-05 in 251346 control chromosomes, predominantly at a frequency of 0.00049 within the South Asian subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in SMPD1 causing Niemann-Pick Disease Type A (0.00049 vs 0.0022). c.1624C>T has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type A (Ranganath_2016). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Niemann-Pick disease, type B Pathogenic:3
| Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Apr 24, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Jan 08, 2021 | A heterozygous missense variation in exon 6 of the SMPD1 gene that results in a stop codon and premature truncation of the protein at codon 2482 was detected. The observed variant c.1624C>T (p.Arg542Ter) has not been reported in the 1000 genomes and has a MAF of 0.006% in the gnomAD databases. The in silico prediction of the variant is disease causing by DANN and MutationTaster. In summary, the variant meets our criteria to be classified as likely pathogenic. - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 17, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 31, 2022 | Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 90 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 33083013, 32860008, 27338287, 31139477, 22796693, 23188845, 33675270, 35534800) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 11, 2022 | - - |
Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 15, 2024 | This sequence change creates a premature translational stop signal (p.Arg542*) in the SMPD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 90 amino acid(s) of the SMPD1 protein. This variant is present in population databases (rs398123478, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease (PMID: 22796693, 23188845, 27338287; 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: 93318). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. - |
See cases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Nov 29, 2019 | ACMG classification criteria: PVS1, PS4, PM2, PM3 - |
Sphingomyelin/cholesterol lipidosis Pathogenic:1
| Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Arg542Ter variant in SMPD1 (also known as p.Arg540Ter due to a difference in cDNA numbering) has been reported in at least 14 individuals with Niemann-Pick disease (PMID: 22796693, 31139477, 27338287) and has been identified in 0.049% (15/30616) of South Asian chromosomes and 0.002% (1/113642) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123478). 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 on ClinVar (VariationID: 93318) as Pathogenic by EGL Genetic Diagnostics and Invitae. This nonsense variant leads to a premature termination codon at position 542. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein without the C-terminus region, which is critical to protein function (PMID: 21098024, 18052040). Loss of function of the SMPD1 gene is an established disease mechanism in autosomal recessive Niemann-Pick disease. The presence of this variant in at least 11 affected homozygotes and in combination with reported pathogenic variants in 3 individuals with Niemann-Pick disease increases the likelihood that the p.Arg542Ter variant is pathogenic (PMID: 22796693, 31139477, 27338287). The phenotype of individuals homozygous and 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: 27338287, 22796693). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences in the homozygous state and with pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PVS1_strong, PM3_strong, PP4, PM2_supporting (Richards 2015). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
Splicing
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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