rs797044798

chr11-6391657-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000543.5(SMPD1):c.592G>C(p.Ala198Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000027 in 1,405,140 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A198A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1 O:1
• Conservation: PhyloP100: 2.77

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000543.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-6391657-G-C is Pathogenic according to our data. Variant chr11-6391657-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203425.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3, not_provided=1, Likely_pathogenic=1}. Variant chr11-6391657-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5	c.592G>C	p.Ala198Pro	missense_variant	2/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9	c.592G>C	p.Ala198Pro	missense_variant	2/6	1	NM_000543.5	P3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2 AN: 144722 Hom.: 0 Cov.: 26 FAILED QC

Gnomad AFR AF: 0.0000515

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000490 AC: 1 AN: 203992 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 112274

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000113

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000270 AC: 38 AN: 1405140 Hom.: 0 Cov.: 36 AF XY: 0.0000272 AC XY: 19 AN XY: 698952

Gnomad4 AFR exome AF: 0.0000308

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: 0.0000335

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000138 AC: 2 AN: 144722 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 70106

Gnomad4 AFR AF: 0.0000515

Gnomad4 AMR AF: 0.00

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

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Niemann-Pick disease, type A Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

Sphingomyelin/cholesterol lipidosis Uncertain:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Some evidence suggests that this pathogenic variant is associated with a less severe form of Niemann-Pick disease type B -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Ala198Pro variant in SMPD1 has been reported in at least 10 individuals with Niemann-Pick disease (PMID: 15234149, 12369017) and has been identified in 0.001133% (1/88272) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs797044798). 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: 203435) as Pathogenic by GeneReviews. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The presence of this variant in 2 affected homozygotes and in combination with a reported pathogenic variant in at least 3 individuals with NIemann-Pick disease increases the likelihood that the p.Ala198Pro variant is pathogenic (VariationID: 167709, 100731; PMID: 15234149, 12369017). In summary, the clinical significance of the p.Ala198Pro variant is uncertain. ACMG/AMP Criteria applied: PM3_strong, PM2, BP4 (Richards 2015). -

Niemann-Pick disease, type B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 21, 2019

Variant summary: SMPD1 c.592G>C (p.Ala198Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 212412 control chromosomes (gnomAD). c.592G>C has been reported in the literature in multiple individuals affected with Niemann-Pick disease type B (McGovern_2004, Simonaro_2002). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission from a reputable database (evaluation after 2014) cites the variant as pathogenic. 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

Invitae

Nov 05, 2023

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 198 of the SMPD1 protein (p.Ala198Pro). 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 missense change has been observed in individual(s) with acid sphingomyelinase deficiency (PMID: 12369017, 15234149; 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: 203425). 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%. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jul 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Benign	0.11
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.021	D;D
Vest4		0.77
MVP		0.75
MPC		0.80
ClinPred		0.94	D
GERP RS		4.3
Varity_R		0.84
gMVP		0.92

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: rs797044798; hg19: chr11-6412887;