rs35122256
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBP6
The ENST00000342245.9(SMPD1):āc.1589G>Cā(p.Gly530Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000266 in 1,614,188 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
ENST00000342245.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMPD1 | NM_000543.5 | c.1589G>C | p.Gly530Ala | missense_variant | 6/6 | ENST00000342245.9 | NP_000534.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMPD1 | ENST00000342245.9 | c.1589G>C | p.Gly530Ala | missense_variant | 6/6 | 1 | NM_000543.5 | ENSP00000340409 | P3 |
Frequencies
GnomAD3 genomes AF: 0.00133 AC: 202AN: 152202Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000318 AC: 80AN: 251306Hom.: 0 AF XY: 0.000199 AC XY: 27AN XY: 135796
GnomAD4 exome AF: 0.000155 AC: 227AN: 1461866Hom.: 1 Cov.: 34 AF XY: 0.000125 AC XY: 91AN XY: 727226
GnomAD4 genome AF: 0.00133 AC: 202AN: 152322Hom.: 0 Cov.: 33 AF XY: 0.00149 AC XY: 111AN XY: 74486
ClinVar
Submissions by phenotype
Niemann-Pick disease, type A Uncertain:1Benign:1
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 16, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 23, 2023 | BS1 - |
Sphingomyelin/cholesterol lipidosis Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Gly530Ala variant in SMPD1 (also known as p.Gly528Ala due to a difference in cDNA numbering) has not been previously reported in individuals with Niemann-Pick disease but has been identified in 0.477% (119/24970) of African chromosomes, 0.023% (8/35428) of African chromosomes, and 0.003% (1/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs35122256). This variant has also been reported in ClinVar (VariationID: 289948) as likely benign by Invitae and EGL Genetic Diagnostics and as a VUS by Illumina Clinical Services Laboratory and Mayo Clinic Genetic Testing Laboratories. The Gly at position 530 is not highly conserved in mammals and evolutionary distant species, and 1 mammal (Prairie Vole) carries an Ala, raising the supporting that this change at this position may be tolerated. Additional computational prediction tools suggest that the variant is less likely to impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Gly530Ala variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1 (Richards 2015). - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 30, 2016 | - - |
SMPD1-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 01, 2021 | 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). - |
Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at