rs146630228
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7
The NM_000543.5(SMPD1):c.297C>G(p.Thr99Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,614,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000543.5 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000690 AC: 105AN: 152162Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000770 AC: 193AN: 250596Hom.: 0 AF XY: 0.000789 AC XY: 107AN XY: 135686
GnomAD4 exome AF: 0.00112 AC: 1643AN: 1461868Hom.: 0 Cov.: 38 AF XY: 0.00112 AC XY: 814AN XY: 727232
GnomAD4 genome AF: 0.000690 AC: 105AN: 152280Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30AN XY: 74446
ClinVar
Submissions by phenotype
Sphingomyelin/cholesterol lipidosis Uncertain:1Benign:1
The c.297C>G (p.Thr99=) variant in SMPD1 (also known as p.Thr97= due to a difference in cDNA numbering) has not been previously reported in individuals with Niemann-Pick disease, but has been identified in 0.141% (181/128754) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs146630228). This variant has also been reported in ClinVar (VariationID: 305196) as a VUS by Illumina Clinical Services Laboratory and as likely benign by Invitae. Computational prediction tools, including splice predictors, and conservation analyses suggest that this synonymous variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4, BP7 (Richards 2015). -
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Niemann-Pick disease, type A Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
SMPD1-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Inborn genetic diseases Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Benign:1
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not provided Benign:1
SMPD1: BP4, BP7 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at