rs199836262
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000543.5(SMPD1):c.8G>A(p.Arg3His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000984 in 1,612,216 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R3R) has been classified as Likely benign.
Frequency
Consequence
NM_000543.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMPD1 | NM_000543.5 | c.8G>A | p.Arg3His | missense_variant | 1/6 | ENST00000342245.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMPD1 | ENST00000342245.9 | c.8G>A | p.Arg3His | missense_variant | 1/6 | 1 | NM_000543.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000605 AC: 92AN: 152076Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000594 AC: 144AN: 242350Hom.: 0 AF XY: 0.000595 AC XY: 79AN XY: 132862
GnomAD4 exome AF: 0.00102 AC: 1495AN: 1460022Hom.: 0 Cov.: 30 AF XY: 0.000966 AC XY: 702AN XY: 726352
GnomAD4 genome ? AF: 0.000604 AC: 92AN: 152194Hom.: 1 Cov.: 33 AF XY: 0.000497 AC XY: 37AN XY: 74404
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 12, 2022 | Identified in the heterozygous state in a patient with intellectual disability, short stature, microcephaly, and dysmorphic features who has other variants that may explain the phenotype (Qiao et al., 2017); Identified in the heterozygous state in a patient with a suspected lysosomal storage disease; however, a second variant was not reported (Fernandez-Marmiesse et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24767253, 28475290) - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 21, 2017 | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Niemann-Pick disease, type A Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 27, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 01, 2018 | - - |
SMPD1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 17, 2023 | The SMPD1 c.8G>A variant is predicted to result in the amino acid substitution p.Arg3His. This variant has been reported in the heterozygous state in an individual with a lysosomal storage disorder, however no additional evidence was provided to support the pathogenicity of this variant (see Table 5 in Fernández-Marmiesse et al. 2014. PubMed ID: 24767253). This variant is reported in 0.11% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-6411836-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Sphingomyelin/cholesterol lipidosis Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | May 05, 2017 | - - |
Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at