rs120074123

Variant names:

• chr11-6393278-A-G
• rs120074123
• NM_000543.5:c.1154A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-6393278-A-G
• chr11-6393278-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000543.5(SMPD1):​c.1154A>G​(p.Asn385Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,684 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: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.92

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 11-6393278-A-G is Pathogenic according to our data. Variant chr11-6393278-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6393278-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.1154A>G	p.Asn385Ser	missense_variant	Exon 3 of 6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9	c.1154A>G	p.Asn385Ser	missense_variant	Exon 3 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461684 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727116

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000454 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type B Pathogenic:1

Jan 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Jul 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asn385 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 1618760). ClinVar contains an entry for this variant (Variation ID: 2988). This variant is also known as N383S. This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 1618760, 33675270). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 385 of the SMPD1 protein (p.Asn385Ser). -

Sphingomyelin/cholesterol lipidosis Pathogenic:1

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Asn385Ser variant in SMPD1 (also known as p.Asn383Ser due to a difference in cDNA numbering) has been reported in at least 1 individual with Niemann-Pick disease (PMID: 26049896, 16010684, 1618760) and was absent from large population studies. This variant has also been reported in ClinVar (VariationID: 2988) as pathogenic by OMIM. In vitro functional studies provide some evidence that the p.Asn385Ser variant may impact protein function (PMID: 26499107, 1618760). However, these types of assays may not accurately represent biological function. 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 p.Asn385Ser variant is located in a region of SMPD1 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 26499107, 15557261). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PM1, PP3 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.90	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0080	D;D
Vest4		0.93
MVP		0.98
MPC		0.71
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.64
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs120074123; hg19: chr11-6414508;