rs780134410
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_000543.5(SMPD1):āc.488T>Cā(p.Leu163Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,520 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes š: 0.0000014 ( 0 hom. )
Consequence
SMPD1
NM_000543.5 missense
NM_000543.5 missense
Scores
8
8
1
Clinical Significance
Conservation
PhyloP100: 4.49
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 Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000543.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.925
PP5
?
Variant 11-6391553-T-C is Pathogenic according to our data. Variant chr11-6391553-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 553935.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMPD1 | NM_000543.5 | c.488T>C | p.Leu163Pro | missense_variant | 2/6 | ENST00000342245.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMPD1 | ENST00000342245.9 | c.488T>C | p.Leu163Pro | missense_variant | 2/6 | 1 | NM_000543.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461520Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2AN XY: 727042
GnomAD4 exome
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2
AN:
1461520
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Cov.:
34
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2
AN XY:
727042
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ExAC
?
AF:
AC:
1
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Niemann-Pick disease, type A Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 20, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 21, 2023 | - - |
Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 27, 2023 | For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt SMPD1 protein function. ClinVar contains an entry for this variant (Variation ID: 553935). This missense change has been observed in individual(s) with Niemann-Pick disease type B (PMID: 21621718, 22818240). This variant is present in population databases (rs780134410, gnomAD 0.0009%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 163 of the SMPD1 protein (p.Leu163Pro). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at