rs786204674

chr11-6393985-C-Tchr11-6393985-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000543.5(SMPD1):c.1430C>T(p.Pro477Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,614,050 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P477Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.45

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.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_000543.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-6393985-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1489165.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 11-6393985-C-T is Pathogenic according to our data. Variant chr11-6393985-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6393985-C-T is described in Lovd as [Pathogenic]. Variant chr11-6393985-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5	c.1430C>T	p.Pro477Leu	missense_variant	5/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9	c.1430C>T	p.Pro477Leu	missense_variant	5/6	1	NM_000543.5	P3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251486 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74322

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000689 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

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

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 21, 2023	Criteria applied: PM3_VSTR,PM2_SUP,PP3,PP4 -
Likely pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Nov 26, 2014	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 10, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2020	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17011332, 22818240, 12369017, 12556236, 15221801, 12712061, 30202406, 30548430) -

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 24, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 477 of the SMPD1 protein (p.Pro477Leu). This variant is present in population databases (rs753508874, gnomAD 0.009%). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 12556236, 12712061, 15221801, 17011332, 22818240). This variant is also known as P475L. ClinVar contains an entry for this variant (Variation ID: 189075). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMPD1 protein function with a positive predictive value of 95%. This variant disrupts the p.Pro477 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been observed in individuals with SMPD1-related conditions (PMID: 27338287), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Sphingomyelin/cholesterol lipidosis Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 22, 2020

The p.Pro477Leu variant in SMPD1 (also known as p.Pro475Leu due to a difference in cDNA numbering) has been reported in at least 9 individuals with Niemann-Pick disease, segregated with disease in 4 affected relatives from 2 families (PMID: 15221801, 12712061, 15234149, 17011332, 22818240), and has been identified in 0.008% (3/35438) of Latino chromosomes, 0.003% (1/30614) of South Asian chromosomes, and 0.002% (2/129190) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs753508874). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 189075) as likely pathogenic by Counsyl and GeneDx. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of individuals homozygous and 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: 22818240). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on its presence in combination with reported pathogenic variants, its presence in individuals with a phenotype highly specific for Niemann-Pick disease, and co-segregation with disease. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP3, PP4, PP1 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.30	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Vest4		0.95
MVP		0.99
MPC		0.81
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.74
gMVP		0.93

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: rs753508874; hg19: chr11-6415215;