11-6391795-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001318088.2(SMPD1):​c.-232G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Consequence

SMPD1
NM_001318088.2 5_prime_UTR_premature_start_codon_gain

Scores

5
1
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 9.25
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
BayesDel_addAF computational evidence supports a deleterious effect, 0.618
PP5
Variant 11-6391795-G-T is Pathogenic according to our data. Variant chr11-6391795-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370798.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.730G>T p.Gly244* stop_gained Exon 2 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.730G>T p.Gly244* stop_gained Exon 2 of 6 1 NM_000543.5 ENSP00000340409.4 P17405-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
36
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Oct 01, 2020
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 22, 2023
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Niemann-Pick disease, type A Pathogenic:2
Apr 14, 2016
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 13, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sphingomyelin/cholesterol lipidosis Pathogenic:1
Jan 22, 2020
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

The p.Gly244Ter variant in SMPD1 (also known as p.Gly242Ter due to a difference in cDNA numbering) has been reported in 1 individual with Niemann-Pick disease (PMID: 29966168) and was absent from large population studies and no high quality genotypes at this site were noted to include this variant. This variant has been reported in ClinVar (VariationID: 370798) as likely pathogenic by Counsyl. This nonsense variant leads to a premature termination codon at position 244, which is predicted to lead to a truncated or absent protein. Loss of function of the SMPD1 gene is an established disease mechanism in autosomal recessive Niemann-Pick disease. The phenotype of an individual compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal, consistent with disease (PMID: 29966168). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on the prediction it causes loss of function, its absence in the general population, and the phenotype of an individual with the variant being highly specific for the disease. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PP4 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Pathogenic
0.65
CADD
Pathogenic
41
DANN
Uncertain
0.99
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
1.0
D
Vest4
0.90
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs120074122; hg19: chr11-6413025; COSMIC: COSV54966614; COSMIC: COSV54966614; API