rs35122256

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBP6

The ENST00000342245.9(SMPD1):ā€‹c.1589G>Cā€‹(p.Gly530Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000266 in 1,614,188 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.0013 ( 0 hom., cov: 33)
Exomes š‘“: 0.00016 ( 1 hom. )

Consequence

SMPD1
ENST00000342245.9 missense

Scores

6
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 2.11
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_benign. Variant got -1 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in ENST00000342245.9
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.010366648).
BP6
Variant 11-6394300-G-C is Benign according to our data. Variant chr11-6394300-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289948.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}. Variant chr11-6394300-G-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMPD1NM_000543.5 linkuse as main transcriptc.1589G>C p.Gly530Ala missense_variant 6/6 ENST00000342245.9 NP_000534.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMPD1ENST00000342245.9 linkuse as main transcriptc.1589G>C p.Gly530Ala missense_variant 6/61 NM_000543.5 ENSP00000340409 P3P17405-1

Frequencies

GnomAD3 genomes
AF:
0.00133
AC:
202
AN:
152202
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00437
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00111
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:
0.00143
GnomAD3 exomes
AF:
0.000318
AC:
80
AN:
251306
Hom.:
0
AF XY:
0.000199
AC XY:
27
AN XY:
135796
show subpopulations
Gnomad AFR exome
AF:
0.00431
Gnomad AMR exome
AF:
0.000231
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000155
AC:
227
AN:
1461866
Hom.:
1
Cov.:
34
AF XY:
0.000125
AC XY:
91
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.00532
Gnomad4 AMR exome
AF:
0.000380
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.000464
GnomAD4 genome
AF:
0.00133
AC:
202
AN:
152322
Hom.:
0
Cov.:
33
AF XY:
0.00149
AC XY:
111
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.00435
Gnomad4 AMR
AF:
0.00111
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:
0.00142
Alfa
AF:
0.000218
Hom.:
0
Bravo
AF:
0.00160
ESP6500AA
AF:
0.00432
AC:
19
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000313
AC:
38
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Niemann-Pick disease, type A Uncertain:1Benign:1
Likely benign, no assertion criteria providedclinical testingNatera, Inc.Nov 16, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMay 23, 2023BS1 -
Sphingomyelin/cholesterol lipidosis Uncertain:1
Uncertain significance, criteria provided, single submittercurationBroad Center for Mendelian Genomics, Broad Institute of MIT and HarvardJan 22, 2020The p.Gly530Ala variant in SMPD1 (also known as p.Gly528Ala due to a difference in cDNA numbering) has not been previously reported in individuals with Niemann-Pick disease but has been identified in 0.477% (119/24970) of African chromosomes, 0.023% (8/35428) of African chromosomes, and 0.003% (1/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs35122256). This variant has also been reported in ClinVar (VariationID: 289948) as likely benign by Invitae and EGL Genetic Diagnostics and as a VUS by Illumina Clinical Services Laboratory and Mayo Clinic Genetic Testing Laboratories. The Gly at position 530 is not highly conserved in mammals and evolutionary distant species, and 1 mammal (Prairie Vole) carries an Ala, raising the supporting that this change at this position may be tolerated. Additional computational prediction tools suggest that the variant is less likely to impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Gly530Ala variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1 (Richards 2015). -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 30, 2016- -
SMPD1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 01, 2021This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 26, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.11
CADD
Benign
14
DANN
Benign
0.95
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.25
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.71
T;T
M_CAP
Benign
0.056
D
MetaRNN
Benign
0.010
T;T
MetaSVM
Uncertain
0.070
D
MutationTaster
Benign
0.83
N;N;N;N
PrimateAI
Benign
0.42
T
PROVEAN
Uncertain
-2.8
D;D
REVEL
Uncertain
0.34
Sift
Uncertain
0.014
D;D
Sift4G
Uncertain
0.054
T;T
Vest4
0.21
MVP
0.99
MPC
0.23
ClinPred
0.060
T
GERP RS
3.8
Varity_R
0.43
gMVP
0.63

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: rs35122256; hg19: chr11-6415530; API