rs120074124

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_001318088.2(SMPD1):c.-51T>C variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000161 in 1,614,056 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: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

SMPD1
NM_001318088.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 3.84

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.905

PP5

Variant 11-6391976-T-C is Pathogenic according to our data. Variant chr11-6391976-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6391976-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5 link	c.911T>C	p.Leu304Pro	missense_variant	Exon 2 of 6	ENST00000342245.9	NP_000534.3	P17405-1Q59EN6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9 link	c.911T>C	p.Leu304Pro	missense_variant	Exon 2 of 6	1	NM_000543.5	ENSP00000340409.4		P17405-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000865

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:

0.0000159

AC:

AN:

251474

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000574

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000865

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:

0.0000999

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type A

Pathogenic:5

Oct 15, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 20, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000543.4(SMPD1):c.911T>C(L304P, aka L302P) is classified as pathogenic in the context of SMPD1-related Niemann-Pick disease. Sources cited for classification include the following: PMID 18815062, 21502868 and 1391960. Classification of NM_000543.4(SMPD1):c.911T>C(L304P, aka L302P) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 05, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.911T>C (p.Leu304Pro, alternatively known as L302P) variant in SMPD1 gene is a missense change that alters a highly conserved nucleotide. The variant, located in the MPP_ASMase domain, is predicted to be deleterious by 5/5 in silico tools. In vitro/vivo functional studies showed that this variant caused severely reduced enzymatic activity. The variant was absent from the large and broad cohorts of the ExAC project (0/121366 chromosomes). The variant was identified in several affected individuals, including multiple homozygotes, with an established diagnosis of NPD-A. Levran (1992) reported the frequency of the variant of interest in affected individuals of Ashkenazi Jewish origin with type A NPD was greater than 20% and called it the second most common disease-causing allele in AJ. Lastly, multiple reputable databases/diagnostic centers classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic. -

Mar 07, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:2

Feb 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 304 of the SMPD1 protein (p.Leu304Pro). This variant is present in population databases (rs120074124, gnomAD 0.04%). This missense change has been observed in individuals with Niemann-Pick type A disease (PMID: 1391960, 8401540, 10464620, 26169695). This variant is also known as p.L302P,. ClinVar contains an entry for this variant (Variation ID: 2989). 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: 1391960, 26499107). For these reasons, this variant has been classified as Pathogenic. -

Jan 19, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Apr 25, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 14, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Common pathogenic variant in Ashkenazi Jewish patients with Niemann-Pick disease, type A (PMID: 1391960); Expression studies show that L304P abolishes sphingomyelin phosphodiesterase 1 enzyme activity (PMID: 1391960); 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: 18815062, 8401540, 23535491, 37347058, 26320887, 36907956, 37069638, 24446175, 30788890, 26169695, 32280632, 1391960) -

Sphingomyelin/cholesterol lipidosis

Pathogenic:1Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

1 of 3 common variants that accounts for more than 90% of pathogenic variants in persons of Ashkenazi Jewish ancestry with Niemann-Pick disease type-A -

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.Leu304Pro variant in SMPD1 (also known as p.Leu302Pro due to a difference in cDNA numbering) has been reported in at least 5 individuals with Niemann-Pick disease (PMID: 8401540, 1391960, 18815062) and has been identified in 0.040% (4/10080) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs120074124). 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: 2989) as Pathogenic by Counsyl, Integrated Genetics, EGL Genetic Diagnostics, OMIM, and GeneReviews. In vitro functional studies provide some evidence that the p.Leu304Pro variant may impact protein function (PMID: 1391960, 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 1 affected homozygote and in combination with a reported pathogenic variant in an individual with Niemann-Pick disease increases the likelihood that the p.Leu304Pro variant is pathogenic (VariaitionID: 2990; PMID: 8401540, 1391960, 18815062). The p.Leu304Pro variant is located in a region of SMPD1 that is essential to protein folding and stability, suggesting that this variant is in functional domain and supports pathogenicity (PMID: 27725636, 30788890). 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. In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on the in vitro functional studies, its importance in maintaining structure, and its presence in affected homozygous and compound heterozygous individuals. ACMG/AMP Criteria applied: PS3, PM3, PM1, PM2_supporting, PP3, PP4 (Richards 2015). -

Niemann-Pick disease, type B

Pathogenic:1

Sep 10, 2015

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

.;D;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.76

T;T;T

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.91

D;D;D

MetaSVM

Uncertain

0.78

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-4.7

D;D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0090

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Vest4

0.98

MVP

0.98

MPC

0.84

ClinPred

0.87

GERP RS

4.9

Varity_R

0.91

gMVP

0.99

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over