rs786204506

Positions:

• chr11-6390694-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000342245.9(SMPD1):​c.96G>A​(p.Trp32Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SMPD1 ENST00000342245.9 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 3.54

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 401 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-6390694-G-A is Pathogenic according to our data. Variant chr11-6390694-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.96G>A	p.Trp32Ter	stop_gained	1/6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9	c.96G>A	p.Trp32Ter	stop_gained	1/6	1	NM_000543.5	ENSP00000340409	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460436 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 726430

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type A Pathogenic:4

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jun 20, 2014	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 02, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 06, 2017	- -

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 28, 2023	This sequence change creates a premature translational stop signal (p.Trp32*) in the SMPD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMPD1 are known to be pathogenic (PMID: 12369017, 15221801). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Niemann-Pick disease (PMID: 15241805, 17876723). ClinVar contains an entry for this variant (Variation ID: 188840). For these reasons, this variant has been classified as Pathogenic. -

SMPD1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 13, 2024

The SMPD1 c.96G>A variant is predicted to result in premature protein termination (p.Trp32*). This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with Niemann-Pick disease type B (see for example, Table 1, Pittis et al. 2004. PubMed ID: 15241805; Fotoulaki et al. 2007. PubMed ID: 17876723; Table 1, Irun et al. 2013. PubMed ID: 23252888). This variant has not been reported in a large population database, indicating this variant is rare. In vitro experimental studies suggest this variant decreases enzymatic activity of the protein (Dardis et al. 2005. PubMed ID: 16010684). Nonsense variants in SMPD1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Niemann-Pick disease, type B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 01, 2020

Variant summary: SMPD1 c.96G>A (p.Trp32X) results in a premature termination codon, predicted to cause an N-terminal truncation of the encoded protein due to translation initiation at a downstream START codon or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 239304 control chromosomes (gnomAD). c.96G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Niemann-Pick Disease Type B (Pittis_2004, Bonetto_2005, Fotoulaki_2007, Irun_2013, Romanello_2016). These data indicate that the variant is very likely to be associated with disease. Publications reported experimental evidence evaluating an impact on protein function, demonstrating a residual enzyme activity of ~20% in leukocytes derived from a homozygous patient (Pittis_2004), though a complete lack of enzyme activity was reported in a eukaryotic cell expression system (Dardis_2005). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.087
FATHMM_MKL	Benign	0.27	N
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.71
GERP RS		4.0

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

LitVar

Other links and lift over

dbSNP: rs786204506; hg19: chr11-6411924;