rs1057516949
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000543.5(SMPD1):c.151_154delGACT(p.Asp51LeufsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000749 in 1,601,852 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000543.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000665 AC: 1AN: 150292Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000805 AC: 2AN: 248452Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134532
GnomAD4 exome AF: 0.00000758 AC: 11AN: 1451560Hom.: 0 AF XY: 0.0000125 AC XY: 9AN XY: 722342
GnomAD4 genome AF: 0.00000665 AC: 1AN: 150292Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 73338
ClinVar
Submissions by phenotype
Niemann-Pick disease, type A Pathogenic:3
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The p.Asp51LeufsTer25 variant in SMPD1 (also known as p.Asp49LeufsTer25 due to a difference in cDNA numbering) has been reported in one Cambodian individual with Niemann-Pick disease (PMID: 24718843) and has been identified in 0.006% (1/15898) of African chromosomes and 0.001% (1/112280) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057516949). 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 in ClinVar (VariationID: 371029) as likely pathogenic by Counsyl. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 51 and leads to a premature termination codon 25 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SMPD1 gene is an established disease mechanism in autosomal recessive Niemann-Pick disease. The phenotype of an individual compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal, consistent with disease (PMID: 24718843). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on the prediction that it will cause loss of function, the phenotype of an individual with the variant being highly specific for disease, and the low frequency of the variant in the general population. ACMG/AMP Criteria applied: PVS1, PM2, PP4 (Richards 2015). -
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Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:1
This sequence change creates a premature translational stop signal (p.Asp51Leufs*25) 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 present in population databases (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with acid sphingomyelinase-deficient Niemann-Pick disease (PMID: 24718843). ClinVar contains an entry for this variant (Variation ID: 371029). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at