rs1554935669

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_000543.5(SMPD1):ā€‹c.1730A>Gā€‹(p.His577Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,614,054 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H577Y) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

SMPD1
NM_000543.5 missense

Scores

5
6
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 7.13
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000543.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.748
PP5
Variant 11-6394441-A-G is Pathogenic according to our data. Variant chr11-6394441-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 550112.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SMPD1NM_000543.5 linkuse as main transcriptc.1730A>G p.His577Arg missense_variant 6/6 ENST00000342245.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SMPD1ENST00000342245.9 linkuse as main transcriptc.1730A>G p.His577Arg missense_variant 6/61 NM_000543.5 P3P17405-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152166
Hom.:
0
Cov.:
33
show subpopulations
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461888
Hom.:
0
Cov.:
34
AF XY:
0.00000275
AC XY:
2
AN XY:
727244
show subpopulations
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152166
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000147
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Niemann-Pick disease, type A Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylDec 29, 2016- -
Likely pathogenic, criteria provided, single submitterclinical testingMendelicsMay 04, 2022- -
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 29, 2024- -
Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:2
Likely pathogenic, criteria provided, single submitterresearchDiagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICSApr 25, 2021- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 16, 2022This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 20386867, 34273913). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 577 of the SMPD1 protein (p.His577Arg). ClinVar contains an entry for this variant (Variation ID: 550112). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His577 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been observed in individuals with SMPD1-related conditions (PMID: 12712061, 20386867, 26499107), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 20386867). 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. -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityNov 03, 2022- -
Sphingomyelin/cholesterol lipidosis Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 28, 2023Variant summary: SMPD1 c.1730A>G (p.His577Arg) results in a non-conservative amino acid change located in the Sphingomyelin phosphodiesterase, C-terminal domain (IPR045473) of 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 251448 control chromosomes (gnomAD). c.1730A>G has been reported in the literature in compound heterozygous and homozygous individuals affected with Niemann-Pick Disease (Desnick_2010, Deshpande_2021). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and p.H577R had less than 1% of expressed wild-type activity (Desnick_2010). The following publications have been ascertained in the context of this evaluation (PMID: 34273913, 20386867, 27435900). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=1, likely pathogenic (n=3) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.31
CADD
Benign
21
DANN
Uncertain
0.99
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.86
D;D
M_CAP
Benign
0.064
D
MetaRNN
Pathogenic
0.75
D;D
MetaSVM
Benign
-0.31
T
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.69
T
PROVEAN
Uncertain
-2.9
D;D
REVEL
Pathogenic
0.80
Sift
Benign
0.27
T;T
Sift4G
Benign
0.43
T;T
Vest4
0.72
MVP
0.99
MPC
0.85
ClinPred
0.89
D
GERP RS
5.4
Varity_R
0.55
gMVP
0.80

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554935669; hg19: chr11-6415671; API