11-6390705-TGCTGGCGCTGGCGCTGGCGCTGGC-TGCTGGCGCTGGCGCTGGCGCTGGCGCTGGCGCTGGC
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP3
The NM_000543.5(SMPD1):c.132_143dupGCTGGCGCTGGC(p.Ala48_Leu49insLeuAlaLeuAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 0)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
SMPD1
NM_000543.5 disruptive_inframe_insertion
NM_000543.5 disruptive_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.158
Genes affected
SMPD1 (HGNC:11120): (sphingomyelin phosphodiesterase 1) The protein encoded by this gene is a lysosomal acid sphingomyelinase that converts sphingomyelin to ceramide. The encoded protein also has phospholipase C activity. Defects in this gene are a cause of Niemann-Pick disease type A (NPA) and Niemann-Pick disease type B (NPB). Multiple transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
BP3
Nonframeshift variant in repetitive region in NM_000543.5
Transcripts
RefSeq
Ensembl
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GnomAD3 genomes 0.000109 AC: 16AN: 147228Hom.: 0 Cov.: 0
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GnomAD4 exome AF: 0.0000207 AC: 30AN: 1447756Hom.: 0 Cov.: 0 AF XY: 0.0000181 AC XY: 13AN XY: 720014
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GnomAD4 genome 0.000109 AC: 16AN: 147228Hom.: 0 Cov.: 0 AF XY: 0.0000835 AC XY: 6AN XY: 71866
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:1Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 26, 2022 | This variant, c.132_143dup, results in the insertion of 4 amino acid(s) of the SMPD1 protein (p.Ala46_Leu49dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with SMPD1-related conditions (PMID: 33675270). ClinVar contains an entry for this variant (Variation ID: 992676). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Huiwen Zhang's lab, Shanghai Jiao Tong University School of Medicine, Xinhua Hospital | Dec 30, 2020 | - - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 30, 2024 | Variant summary: SMPD1 c.132_143dup12 (p.Ala46_Leu49dup) results in an in-frame duplication that is predicted to insert four amino acids into the (putative) signal peptide region (Rhein_2014) of the encoded protein. The variant allele was found at a frequency of 0.00011 in 146056 control chromosomes (gnomAD v3.1). However, it is located in a polymorphic region where it is in overlap with other frequent in-frame deletion-insertion variants. c.132_143dup12 has been reported in the literature as a compound heterozygous genotype in an individual affected with Niemann-Pick Disease (Hu_2021). This report does not provide unequivocal conclusions about association of the variant with Niemann-Pick Disease. A functional study analyzed the effect of variable numbers of Leu-Ala (LA) repeats in the signal peptide region, and found that variants encoding 2, 8 or 9 repeats resulted in significantly lowered ASM secretion rates compared to the wild-type with 6 LA-repeat (Rhein_2014). The following publications have been ascertained in the context of this evaluation (PMID: 33675270, 27814975, 25301364). ClinVar contains an entry for this variant (Variation ID: 992676). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 08, 2021 | - - |
Niemann-Pick disease, type A Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 17, 2020 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at