rs120074126

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000543.5(SMPD1):c.1267C>T(p.His423Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,611,816 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H423R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SMPD1
NM_000543.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 7.13

Publications

17 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)

SMPD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 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 chr11-6393621-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2136989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.91

PP5

Variant 11-6393620-C-T is Pathogenic according to our data. Variant chr11-6393620-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2992.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
SMPD1	NM_000543.5 link	c.1267C>T	p.His423Tyr	missense_variant	Exon 4 of 6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9 link	c.1267C>T	p.His423Tyr	missense_variant	Exon 4 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

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

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1459646

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726300

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33426

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1109998

Other (OTH)

AF:

0.0000166

AC:

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00000938

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type A

Pathogenic:5

Mar 17, 2017

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 07, 2021

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A Heterozygous missense variation in exon 4 of the SMPD1 gene that results in the amino acid substitution of Tyrosine for Histidine at codon 423 was detected. The observed variant c.1267C>T (p.His423Tyr) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are possibly damaging by DANN, FATHMM, PROVEAN. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pathology and Clinical Laboratory Medicine, King Fahad Medical City

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Enzyme deficiency -

Feb 21, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Niemann-Pick disease, type B

Pathogenic:4

Dec 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 26, 2016

Counsyl

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 01, 2020

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SMPD1 c.1267C>T (p.His423Tyr) results in a conservative amino acid change located in the Acid sphingomyelinase/endophosphatase, metallophosphatase domain (IPR041805) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 249054 control chromosomes. c.1267C>T has been reported in the literature in multiple individuals affected with Niemann-Pick Disease (example, Fotoulaki_2007, Simonaro_2002) and has been cited by as one of the most common type B NPD allele among the Saudi population. These data indicate that the variant is very 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 activity in both in-vitro and in-situ enzyme assays (Jones_2008). Four 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=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Pathology and Clinical Laboratory Medicine, King Fahad Medical City

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Enzyme deficiency -

not provided

Pathogenic:3

Mar 02, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 09, 2016

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 14, 2019

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect (Jones et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33101984, 32292456, 26981555, 26499107, 27338287, 28600779, 17876723, 20301544, 12369017, 18815062) -

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

Pathogenic:2

Sep 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 423 of the SMPD1 protein (p.His423Tyr). This variant is present in population databases (rs120074126, gnomAD 0.0009%). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 12369017, 17876723, 27338287, 28600779). This variant is also known as p.His421Tyr. ClinVar contains an entry for this variant (Variation ID: 2992). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SMPD1 protein function with a positive predictive value of 95%. This variant disrupts the p.His423 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been observed in individuals with SMPD1-related conditions (PMID: 16434659), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Apr 25, 2021

Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Sphingomyelin/cholesterol lipidosis

Pathogenic:1Other: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.His423Tyr variant in SMPD1 (also known as p.His421Tyr due to a difference in cDNA numbering) has been reported in at least 13 individuals with Niemann-Pick disease (PMID: 12369017, 27338287, 26981555, 17876723) and has been identified in 0.002% (1/66538) of European (non-Finnish) chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs120074126). 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: 2992) as likely pathogenic by Invitae and as pathogenic by Counsyl, EGL Genetic Diagnostics, OMIM and GeneReviews. In vitro functional studies provide some evidence that the p.His423Tyr variant may impact protein function (PMID: 18815062). 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. The presence of this variant in at least 12 affected homozygotes and with another pathogenic variant in an affected individual increases the likelihood that the p.His423 variant is pathogenic (VariationID: 188840; PMID: 12369017, 27338287, 26981555, 17876723). The phenotype of an individual homozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal, consistent with disease (PMID: 27338287, 17876723). The p.His423Tyr 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 supports pathogenicity (PMID: 12369017, 18815062). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on functional studies, its location in an active site and zinc binding site, its presence in affected homozygotes, and its presence in patients with a phenotype highly specific for disease. ACMG/AMP Criteria applied: PS3, PM2, PM1, PM3, PP3, PP4 (Richards 2015). -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Found most commonly in persons from Saudi Arabia. Leads to early-onset severe form of Niemann-Pick disease type-A -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.082

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.15

PhyloP100

7.1

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.9

D;D

REVEL

Pathogenic

0.82

Sift

Benign

0.058

T;T

Sift4G

Benign

0.13

T;T

Vest4

0.93

MVP

0.96

MPC

0.71

ClinPred

0.98

GERP RS

4.8

Varity_R

0.81

gMVP

0.94

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over