rs398123479

chr11-6391822-G-C

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.757G>C(p.Asp253His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,246 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. D253E) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.26

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, 3 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 chr11-6391824-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 997803.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 11-6391822-G-C is Pathogenic according to our data. Variant chr11-6391822-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 93320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6391822-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5	c.757G>C	p.Asp253His	missense_variant	2/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9	c.757G>C	p.Asp253His	missense_variant	2/6	1	NM_000543.5	P3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 31

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249222 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135216

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000513 AC: 75 AN: 1461014 Hom.: 0 Cov.: 36 AF XY: 0.0000619 AC XY: 45 AN XY: 726896

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000656

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74376

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type A Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 24, 2017	The p.Asp253His (NM_000543.4 c.757G>C) variant in SMPD1 has been reported in one compound heterozygous individual with acid sphingomyelinase deficiency (Niemann -Pick disease) (Desnick 2010) and one individual who had a child with Niemann-Pi ck disease type A, whose partner carried a pathogenic variant in the gene (ClinV ar https://www.ncbi.nlm.nih.gov/clinvar/variation/93320/ and personal communicat ion with Emory Genetics Laboratory). This variant has been identified in 1/65,79 4 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs398123479). Computational prediction tools and cons ervation analysis suggest that the p.Asp253His variant may impact the protein, t hough this information is not predictive enough to determine pathogenicity. In v itro functional studies provide some evidence that the p.Asp253His variant may i mpact protein function (Desnick 2010). However, these types of assays may not ac curately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, the p.Asp253His vari ant is likely pathogenic for autosomal recessive acid sphingomyelinase deficienc y, based upon observation in patients and supportive population, functional and predictive data. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 18, 2021	Variant summary: SMPD1 c.757G>C (p.Asp253His) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type (IPR004843) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249222 control chromosomes. c.757G>C has been reported in the literature as a compound heterozygous genotype in at-least two clinically well characterized individuals affected with Niemann-Pick Disease Type A (example, Desnick_2010, Thurberg_2020). One of these two individuals displayed a characteristic autopsy pathology of infantile neurovisceral acid sphingomyelinase deficiency (Thurberg_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal acid sphingomyelinase enzyme activity in an in-vitro experimental system (example, Desnick_2010). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jul 24, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 27, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2019	Reported previously in association with Niemann-Pick disease, types A/B, and expression studies in 293-T cells show that D253H is associated with less than 1% of wild-type acid sphingomyelinase enzyme activity (Desnick et al., 2010); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23356216, 23770607, 20386867, 23757202, 26499107, 30609409, 27659707, 32714837) -

Niemann-Pick disease, type B Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Counsyl

Jul 24, 2019

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 05, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 253 of the SMPD1 protein (p.Asp253His). This variant is present in population databases (rs398123479, gnomAD 0.004%). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 20386867, 32714837). ClinVar contains an entry for this variant (Variation ID: 93320). 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%. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 20386867). This variant disrupts the p.Asp253 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been observed in individuals with SMPD1-related conditions (PMID: 23356216), 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.Asp253His variant in SMPD1 (also known as p.Asp251His due to a difference in cDNA numbering) has been reported in 1 individual with Niemann-Pick disease (PMID: 20386867), in 1 individual with a child with Niemann-Pick disease whose other parent also had a pathogenic variant in SMPD1 (VariationID: 93320), and has been identified in 0.004% (4/113028) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123479). 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: 93320) as likely pathogenic by the Laboratory for Molecular Medicine and Integrated Genetics and as pathogenic by EGL Genetic Diagnostics and GeneDx. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Asp253Glu, has been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (PMID: 15877209, 15557261, 27349982). In vitro functional studies provide some evidence that the p.Asp253His variant may impact protein function (PMID: 20386867). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant was reported in combination with a reported likely pathogenic variant in an individual with Niemann-Pick disease (PMID: 20386867). The p.Asp253His variant is located in a region of SMPD1 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 27349982, 15557261). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on in vitro functional studies, the presence of another pathogenic variant in the same codon, and the residue being important for protein function and folding. ACMG/AMP Criteria applied: PS3, PM2, PM5, PP3, PM1_supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.99
MVP		0.99
MPC		0.88
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99

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: rs398123479; hg19: chr11-6413052;