rs398123478

Variant names:

• chr11-6394335-C-T
• rs398123478
• NM_000543.5:c.1624C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000543.5(SMPD1):​c.1624C>T​(p.Arg542*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000229 in 1,614,218 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: SMPD1 NM_000543.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 3.67

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-6394335-C-T is Pathogenic according to our data. Variant chr11-6394335-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 93318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6394335-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.1624C>T	p.Arg542*	stop_gained	Exon 6 of 6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9	c.1624C>T	p.Arg542*	stop_gained	Exon 6 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152210 Hom.: 0 Cov.: 33

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: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000637 AC: 16 AN: 251346 Hom.: 0 AF XY: 0.0000884 AC XY: 12 AN XY: 135812

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: 0.000490

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461890 Hom.: 0 Cov.: 34 AF XY: 0.0000358 AC XY: 26 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type A Pathogenic:7

Jun 02, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed stop gained variant c.1624C>T(p.Arg542Ter) in the SMPD1 gene has been reported previously in multiple individuals affected with Niemann-Pick disease. In this study the p. (Arg542*) (c.1624C>T) mutation was the most commonly identified mutation, found in 22% (26 out of 120) of the alleles tested, but haplotype analysis for this mutation did not identify a founder effect for the Indian population (Ranganath P, et al., 2016). Though this variant is present in the last exon, there are other pathogenic variants reported beyond this position in the ClinVar database. This variant is reported with the allele frequency 0.01% in the gnomAD Exomes. It is submitted to ClinVar as Pathogenic/Likely pathogenic. Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 24, 2015

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 31, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000093318 /PMID: 22796693). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Oct 27, 2023

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 homozygous variation in exon 6 of the SMPD1 gene that results in a premature truncation of the protein at codon 542 was detected. The observed variant c.1624C>T(p.Arg542Ter) has not been reported in the 1000 genomes and has a MAF of 0.006% in gnomAD database. The in silico prediction of the variant is disease causing by DANN and MutationTaster. In summary, the variant meets our criteria to be classified as pathogenic. -

Apr 29, 2019

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.1624C>T (p.Arg542X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.4e-05 in 251346 control chromosomes, predominantly at a frequency of 0.00049 within the South Asian subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in SMPD1 causing Niemann-Pick Disease Type A (0.00049 vs 0.0022). c.1624C>T has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type A (Ranganath_2016). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Niemann-Pick disease, type B Pathogenic:3

-

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 24, 2015

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 08, 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 6 of the SMPD1 gene that results in a stop codon and premature truncation of the protein at codon 2482 was detected. The observed variant c.1624C>T (p.Arg542Ter) has not been reported in the 1000 genomes and has a MAF of 0.006% in the gnomAD databases. The in silico prediction of the variant is disease causing by DANN and MutationTaster. In summary, the variant meets our criteria to be classified as likely pathogenic. -

not provided Pathogenic:3

Sep 11, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 17, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 90 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 33083013, 32860008, 27338287, 31139477, 22796693, 23188845, 33675270, 35534800) -

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:2

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Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg542*) in the SMPD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 90 amino acid(s) of the SMPD1 protein. This variant is present in population databases (rs398123478, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease (PMID: 22796693, 23188845, 27338287; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 93318). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

See cases Pathogenic:1

Nov 29, 2019

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1, PS4, PM2, PM3 -

Sphingomyelin/cholesterol lipidosis Pathogenic: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.Arg542Ter variant in SMPD1 (also known as p.Arg540Ter due to a difference in cDNA numbering) has been reported in at least 14 individuals with Niemann-Pick disease (PMID: 22796693, 31139477, 27338287) and has been identified in 0.049% (15/30616) of South Asian chromosomes and 0.002% (1/113642) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123478). 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 on ClinVar (VariationID: 93318) as Pathogenic by EGL Genetic Diagnostics and Invitae. This nonsense variant leads to a premature termination codon at position 542. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein without the C-terminus region, which is critical to protein function (PMID: 21098024, 18052040). Loss of function of the SMPD1 gene is an established disease mechanism in autosomal recessive Niemann-Pick disease. The presence of this variant in at least 11 affected homozygotes and in combination with reported pathogenic variants in 3 individuals with Niemann-Pick disease increases the likelihood that the p.Arg542Ter variant is pathogenic (PMID: 22796693, 31139477, 27338287). The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being less than 10% of normal, consistent with disease (PMID: 27338287, 22796693). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences in the homozygous state and with pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PVS1_strong, PM3_strong, PP4, PM2_supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.79	D
Vest4		0.91
GERP RS		4.0

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: rs398123478; hg19: chr11-6415565;