chr11-6393981-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000543.5(SMPD1):c.1426C>T(p.Arg476Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,614,174 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 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

SMPD1
NM_000543.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 5.68

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 16 ACMG points.

PM1

In a strand (size 7) in uniprot entity ASM_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000543.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.944

PP5

Variant 11-6393981-C-T is Pathogenic according to our data. Variant chr11-6393981-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 93315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6393981-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5 link	c.1426C>T	p.Arg476Trp	missense_variant	Exon 5 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.1426C>T	p.Arg476Trp	missense_variant	Exon 5 of 6	1	NM_000543.5	ENSP00000340409.4		P17405-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251492

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000578

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

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:

0.00000540

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000688

Hom.:

Bravo

AF:

0.000132

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type A

Pathogenic:3

Mar 25, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 11, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

not provided

Pathogenic:2

Dec 18, 2012

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 26, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sphingomyelin/cholesterol lipidosis

Pathogenic:1Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Some evidence suggests that this pathogenic variant is associated with a less severe form of Niemann-Pick disease type-B -

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.Arg476Trp variant in SMPD1 (also known as p.Arg474Trp due to a difference in cDNA numbering) has been reported in at least 11 individuals with Niemann-Pick disease (PMID: 31122880, 12712061, 23252888, 19405096, 29995201, 12369017, 15877209) and has been identified in 0.012% (3/24964) of African chromosomes and 0.006% (2/35438) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs182812968). 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 (Variation ID: 93315) as pathogenic by Integrated Genetics, EGL Genetic Diagnostics, and GeneReviews, and likely pathogenic by Counsyl and Invitae. 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 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: 19405096, 15877209). The presence of this variant in combination with reported pathogenic variants in at least 7 individuals with Niemann-Pick disease increases the likelihood that the p.Arg476Trp variant is pathogenic (VariationID: 242451, 2980, 2990, 2993, 198093, 100731, 195086; PMID: 31122880, 12712061, 23252888, 19405096, 29995201, 12369017). 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 other pathogenic variants, low frequency in the general population, and the phenotype of individuals with the variant being highly specific for disease. ACMG/AMP Criteria applied: PM3_very-strong, PM2_supporting, PP3, PP4 (Richards 2015). -

not specified

Pathogenic:1

Sep 22, 2017

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 SMPD1 c.1426C>T (p.Arg476Trp) variant involves the alteration of a conserved nucleotide located in the Metallo-dependent phosphatase-like (InterPro). 4/4 in silico tools predict a damaging outcome for this variant. This variant was found in 6/277218 control chromosomes at a frequency of 0.0000216, which does not exceed the estimated maximal expected allele frequency of a pathogenic SMPD1 variant (0.0022361). The variant has been reported in numerous affected compound heterozygote individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. -

SMPD1-related disorder

Pathogenic:1

Jan 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SMPD1 c.1426C>T variant is predicted to result in the amino acid substitution p.Arg476Trp. This variant has been reported to be causative for autosomal recessive Niemann-Pick disease, primarily the milder type B disorder (also described as p.Arg474Trp, Simonaro et al. 2002. PubMed ID: 12369017; Rodríguez-Pascau et al. 2009. PubMed ID: 19405096; Irun et al. 2013. PubMed ID: 23252888). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. Based on the available evidence, we classify this variant as pathogenic. -

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

Pathogenic:1

Feb 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 476 of the SMPD1 protein (p.Arg476Trp). This variant is present in population databases (rs182812968, gnomAD 0.01%). This missense change has been observed in individual(s) with Niemann-Pick disease type B (PMID: 12369017, 12712061, 15234149, 23252888; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Arg474Trp. ClinVar contains an entry for this variant (Variation ID: 93315). 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.Arg476 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been observed in individuals with SMPD1-related conditions (PMID: 12712061, 26499107), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

1.0

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-7.1

D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Vest4

0.94

MVP

0.98

MPC

0.82

ClinPred

0.93

GERP RS

4.7

Varity_R

0.90

gMVP

0.83

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

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