chr11-6391637-CT-C

Variant names:

• chr11-6391637-CT-C
• rs727504167
• NM_000543.5:c.573delT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000543.5(SMPD1):​c.573delT​(p.Ser192AlafsTer65) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P191P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000043 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMPD1 NM_000543.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: -0.266
• Publications: 10 publications found

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)

ACMG classification

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

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-6391637-CT-C is Pathogenic according to our data. Variant chr11-6391637-CT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 167710.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	c.573delT	p.Ser192AlafsTer65	frameshift_variant	Exon 2 of 6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9	c.573delT	p.Ser192AlafsTer65	frameshift_variant	Exon 2 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes AF: 0.00000666 AC: 1 AN: 150134 Hom.: 0 Cov.: 0

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: 0.0000149

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000135 AC: 2 AN: 147884 AF XY: 0.0000125

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.000234

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000425 AC: 59 AN: 1387686 Hom.: 0 Cov.: 10 AF XY: 0.0000379 AC XY: 26 AN XY: 685218

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000128 AC: 4 AN: 31342

American (AMR) AF: 0.00 AC: 0 AN: 36042

Ashkenazi Jewish (ASJ) AF: 0.0000801 AC: 2 AN: 24976

East Asian (EAS) AF: 0.00 AC: 0 AN: 35608

South Asian (SAS) AF: 0.00 AC: 0 AN: 79346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45798

Middle Eastern (MID) AF: 0.000485 AC: 2 AN: 4122

European-Non Finnish (NFE) AF: 0.0000466 AC: 50 AN: 1073024

Other (OTH) AF: 0.0000174 AC: 1 AN: 57428

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000666 AC: 1 AN: 150234 Hom.: 0 Cov.: 0 AF XY: 0.0000136 AC XY: 1 AN XY: 73374

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 40900

American (AMR) AF: 0.00 AC: 0 AN: 15062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5056

South Asian (SAS) AF: 0.00 AC: 0 AN: 4716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67330

Other (OTH) AF: 0.00 AC: 0 AN: 2062

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000505 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type A Pathogenic:4

Jul 18, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SMPD1 c.573delT (p.Ser192AlafsTer65) variant (also reported as 677delT; c.567delT; p.P189fs; fsP189) results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Ser192AlafsTer65 variant has been identified in a total of 26 individuals with acid sphingomyelinase deficiency including 20 homozygotes and one compound heterozygote with Niemann-Pick disease type A and five compound heterozygotes with Niemann-Pick disease type B, (Gluck et al. 1998; Ricci et al. 2004; Pittis et al. 2004; Desnick et al. 2010; Oyama et al. 2012; Dalal et al. 2015; Zampieri et al. 2016). Twelve of the homozygous patients are of Israeli Arab ethnicity from the lower Galilee and Samaria region, an area where consanguinity is common although none of these families were noted as consanguineous. The other eight homozygous patients, as well as at least one of the compound heterozygous patients are from Southern Italy, where it has been suggested the population is genetically similar to the Middle East. The second variant found in the compound heterozygous patients was either a missense variant (four individuals), a nonsense variant (one individual) or a frameshift variant (one individual). Two of the compound heterozygous individuals were noted to have 11% and 21.7% residual enzyme activity compared to wild type respectively (Pittis et al. 2004; Desnick et al. 2010). The p.Ser192AlafsTer65variant was absent from 50 healthy Italian controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium or the Genome Aggregation Database. Based on the evidence from the literature and the potential impact of frameshift variants, the p.Ser192AlafsTer65 variant is classified as pathogenic for SMPD1-Related Disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Jan 31, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 29, 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.573delT (p.Ser192Alafs) variant (alternatively also known as 667delA and 567delA) results in a premature termination codon, predicted to cause a truncated or absent SMPD1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic/likely pathogenic by our laboratory (e.g. c.996delC, c.1785_1786delCC, etc.). This variant is absent from 23568 control chromosomes from ExAC. This variant has been reported in several patients with Niemann-Pick disease (NPD). In homozygous state and in compound heterozygous with other severe mutations, it is found to cause type 1 NPD. It was found to be a common pathogenic variant in Israeli Arabs and Turkish patient population (Gluck_1998, Aykut_2013). On clinical laboratory in ClinVar has classified it as pathogenic. Taken together, this variant is classified as pathogenic.

Mar 16, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Pathogenic:3

Nov 25, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SMPD1: PVS1, PM3:Strong, PM2, PP4:Moderate

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

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

Mar 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 30, 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.Ser192Alafs*65) in the SMPD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMPD1 are known to be pathogenic (PMID: 12369017, 15221801). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with Niemann-Pick disease (PMID: 10694919, 20386867, 25811928, 26913189). This variant is also known as c.677delT. ClinVar contains an entry for this variant (Variation ID: 167710). For these reasons, this variant has been classified as Pathogenic.

Niemann-Pick disease, type B Pathogenic:1

Jan 09, 2018

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.

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.Ser192AlafsTer65 variant in SMPD1 (also known as p.Ser190AlafsTer65 due to a difference in cDNA numbering) has been reported in at least 12 individuals with Niemann-Pick disease (PMID: 15241805, 15221801, 26913189, 26499107), but data from large population studies is insufficient to assess the frequency of this variant. This variant has also been reported in ClinVar (VariationID: 167710) as pathogenic by EGL Genetic Diagnostics, Integrated Genetics, Counsyl, and Illumina Clinical Services Laboratory. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 192 and leads to a premature termination codon 65 amino acids downstream. Loss of function of the SMPD1 gene is an established disease mechanism in autosomal recessive Niemann-Pick disease. The presence of this variant in 8 affected homozygotes and in combination with a reported pathogenic variant and in an individual with Niemann-Pick disease increases the likelihood that the p.Ser192Alafs variant is pathogenic (VariationID: 188840; PMID: 15241805, 15221801). The phenotype of an individual 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: 26913189). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on the prediction that it will cause loss of function, the presence of the variant in affected homozygotes and compound heterozygous, and the phenotype of individuals with the variant being highly specific for disease. ACMG/AMP Criteria applied: PVS1, PM3, PP4 (Richards 2015).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.27
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs727504167; hg19: chr11-6412867;