NM_000543.5:c.730G>T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000543.5(SMPD1):c.730G>T(p.Gly244*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000543.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 36
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not provided Pathogenic:2
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Niemann-Pick disease, type A Pathogenic:2
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Sphingomyelin/cholesterol lipidosis Pathogenic:1
The p.Gly244Ter variant in SMPD1 (also known as p.Gly242Ter due to a difference in cDNA numbering) has been reported in 1 individual with Niemann-Pick disease (PMID: 29966168) and was absent from large population studies and no high quality genotypes at this site were noted to include this variant. This variant has been reported in ClinVar (VariationID: 370798) as likely pathogenic by Counsyl. This nonsense variant leads to a premature termination codon at position 244, which is 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: 29966168). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on the prediction it causes loss of function, its absence in the general population, and the phenotype of an individual with the variant being highly specific for the disease. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PP4 (Richards 2015). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at