GeneBe

rs1422720020

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000543.5(SMPD1):​c.1101delG​(p.Phe368SerfsTer17) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G367G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

SMPD1
NM_000543.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 9.48

Publications

2 publications found
Variant links:
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 deficiency
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • Niemann-Pick disease
    Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
  • Niemann-Pick disease type A
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
  • Niemann-Pick disease type B
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

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 11-6393219-TG-T is Pathogenic according to our data. Variant chr11-6393219-TG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 992699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMPD1NM_000543.5 linkc.1101delG p.Phe368SerfsTer17 frameshift_variant Exon 3 of 6 ENST00000342245.9 NP_000534.3 P17405-1Q59EN6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMPD1ENST00000342245.9 linkc.1101delG p.Phe368SerfsTer17 frameshift_variant Exon 3 of 6 1 NM_000543.5 ENSP00000340409.4 P17405-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1461486
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727042
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44708
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26126
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86228
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53398
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111710
Other (OTH)
AF:
0.00
AC:
0
AN:
60368
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:1
Dec 30, 2020
Huiwen Zhang's lab, Shanghai Jiao Tong University School of Medicine, Xinhua Hospital
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Niemann-Pick disease, type A Pathogenic:1
Feb 28, 2024
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
9.5

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1422720020; hg19: chr11-6414449; COSMIC: COSV54970925; COSMIC: COSV54970925; API