rs786204514

Positions:

• chr11-6393232-GCT-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000543.5(SMPD1):​c.1111_1112del​(p.Leu371PhefsTer19) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000479 in 1,461,612 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SMPD1 NM_000543.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.74

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-6393232-GCT-G is Pathogenic according to our data. Variant chr11-6393232-GCT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6393232-GCT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.1111_1112del	p.Leu371PhefsTer19	frameshift_variant	3/6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9	c.1111_1112del	p.Leu371PhefsTer19	frameshift_variant	3/6	1	NM_000543.5	ENSP00000340409	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461612 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 727098

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type A Pathogenic:2

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jun 26, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 31, 2020	Variant summary: SMPD1 c.1111_1112delCT (p.Leu371PhefsX19) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 249166 control chromosomes. c.1111_1112delCT has been reported in the literature in at-least one individual affected with Niemann-Pick Disease Type A and has been subsequently cited by others (example, Ricci_2004, Zampieri_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 18, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188853). This variant is also known as c.1110_1111delTC. This premature translational stop signal has been observed in individual(s) with clinical features of Niemann-Pick disease (PMID: 34554397). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu371Phefs*19) 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). -

Computational scores

Source: dbNSFP v4.3

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: rs786204514; hg19: chr11-6414462;