chr11-6391904-A-ACATCCCCG
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000543.5(SMPD1):c.842_849dupTCCCCGCA(p.His284SerfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,072 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. H284H) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Consequence
SMPD1
NM_000543.5 frameshift
NM_000543.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.77
Publications
4 publications found
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]
SMPD1 Gene-Disease associations (from GenCC):
- acid sphingomyelinase deficiencyInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- Niemann-Pick diseaseInheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
- Niemann-Pick disease type AInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
- Niemann-Pick disease type BInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-6391904-A-ACATCCCCG is Pathogenic according to our data. Variant chr11-6391904-A-ACATCCCCG is described in ClinVar as Pathogenic. ClinVar VariationId is 93321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000543.5. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SMPD1 | NM_000543.5 | MANE Select | c.842_849dupTCCCCGCA | p.His284SerfsTer18 | frameshift | Exon 2 of 6 | NP_000534.3 | ||
| SMPD1 | NM_001007593.3 | c.839_846dupTCCCCGCA | p.His283SerfsTer18 | frameshift | Exon 2 of 6 | NP_001007594.2 | |||
| SMPD1 | NM_001365135.2 | c.842_849dupTCCCCGCA | p.His284SerfsTer18 | frameshift | Exon 2 of 5 | NP_001352064.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SMPD1 | ENST00000342245.9 | TSL:1 MANE Select | c.842_849dupTCCCCGCA | p.His284SerfsTer18 | frameshift | Exon 2 of 6 | ENSP00000340409.4 | ||
| SMPD1 | ENST00000526280.1 | TSL:1 | c.29_36dupTCCCCGCA | p.His13ProfsTer4 | frameshift | Exon 1 of 4 | ENSP00000436278.1 | ||
| SMPD1 | ENST00000533123.5 | TSL:1 | n.842_849dupTCCCCGCA | non_coding_transcript_exon | Exon 2 of 5 | ENSP00000435950.1 |
Frequencies
GnomAD3 genomes 0.00000658 AC: 1AN: 152072Hom.: 0 Cov.: 31 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152072
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
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Gnomad SAS
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Gnomad NFE
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Gnomad OTH
AF:
GnomAD4 exome Cov.: 36
GnomAD4 exome
Cov.:
36
GnomAD4 genome 0.00000658 AC: 1AN: 152072Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74298 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
152072
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
74298
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41408
American (AMR)
AF:
AC:
0
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3466
East Asian (EAS)
AF:
AC:
1
AN:
5192
South Asian (SAS)
AF:
AC:
0
AN:
4818
European-Finnish (FIN)
AF:
AC:
0
AN:
10604
Middle Eastern (MID)
AF:
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
AC:
0
AN:
68000
Other (OTH)
AF:
AC:
0
AN:
2084
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
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0.60
0.80
0.95
Allele balance
Age Distribution
Genome Het
Variant carriers
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Age
Alfa
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ClinVar
ClinVar submissions as Germline
Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
3
-
-
Niemann-Pick disease, type A (3)
1
-
-
Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B (1)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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