rs748165078
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000543.5(SMPD1):c.581del(p.Pro194GlnfsTer63) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S192S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 30)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SMPD1
NM_000543.5 frameshift
NM_000543.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.220
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 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 11-6391640-GC-G is Pathogenic according to our data. Variant chr11-6391640-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMPD1 | NM_000543.5 | c.581del | p.Pro194GlnfsTer63 | frameshift_variant | 2/6 | ENST00000342245.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMPD1 | ENST00000342245.9 | c.581del | p.Pro194GlnfsTer63 | frameshift_variant | 2/6 | 1 | NM_000543.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD3 genomes
?
Cov.:
30
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 514240Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0AN XY: 264552
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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38
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264552
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GnomAD4 genome ? Cov.: 30
GnomAD4 genome
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30
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 25, 2023 | This sequence change creates a premature translational stop signal (p.Pro194Glnfs*63) 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 individual(s) with Niemann-Pick disease (PMID: 15221801, 30795770). This variant is also known as c.575delC (p.P192fsX62). ClinVar contains an entry for this variant (Variation ID: 371211). For these reasons, this variant has been classified as Pathogenic. - |
Niemann-Pick disease, type A Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 29, 2016 | - - |
Computational scores
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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