rs786204506
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000342245.9(SMPD1):c.96G>A(p.Trp32Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,436 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
SMPD1
ENST00000342245.9 stop_gained
ENST00000342245.9 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: 3.54
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 18 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 401 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-6390694-G-A is Pathogenic according to our data. Variant chr11-6390694-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMPD1 | NM_000543.5 | c.96G>A | p.Trp32Ter | stop_gained | 1/6 | ENST00000342245.9 | NP_000534.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMPD1 | ENST00000342245.9 | c.96G>A | p.Trp32Ter | stop_gained | 1/6 | 1 | NM_000543.5 | ENSP00000340409 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460436Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4AN XY: 726430
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
Bravo
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Niemann-Pick disease, type A Pathogenic:4
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jun 20, 2014 | - - |
Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 02, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 06, 2017 | - - |
Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 08, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 28, 2023 | This sequence change creates a premature translational stop signal (p.Trp32*) in the SMPD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMPD1 are known to be pathogenic (PMID: 12369017, 15221801). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Niemann-Pick disease (PMID: 15241805, 17876723). ClinVar contains an entry for this variant (Variation ID: 188840). For these reasons, this variant has been classified as Pathogenic. - |
SMPD1-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 13, 2024 | The SMPD1 c.96G>A variant is predicted to result in premature protein termination (p.Trp32*). This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with Niemann-Pick disease type B (see for example, Table 1, Pittis et al. 2004. PubMed ID: 15241805; Fotoulaki et al. 2007. PubMed ID: 17876723; Table 1, Irun et al. 2013. PubMed ID: 23252888). This variant has not been reported in a large population database, indicating this variant is rare. In vitro experimental studies suggest this variant decreases enzymatic activity of the protein (Dardis et al. 2005. PubMed ID: 16010684). Nonsense variants in SMPD1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Niemann-Pick disease, type B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 01, 2020 | Variant summary: SMPD1 c.96G>A (p.Trp32X) results in a premature termination codon, predicted to cause an N-terminal truncation of the encoded protein due to translation initiation at a downstream START codon or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 239304 control chromosomes (gnomAD). c.96G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Niemann-Pick Disease Type B (Pittis_2004, Bonetto_2005, Fotoulaki_2007, Irun_2013, Romanello_2016). These data indicate that the variant is very likely to be associated with disease. Publications reported experimental evidence evaluating an impact on protein function, demonstrating a residual enzyme activity of ~20% in leukocytes derived from a homozygous patient (Pittis_2004), though a complete lack of enzyme activity was reported in a eukaryotic cell expression system (Dardis_2005). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A;A;A
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