rs1050239

chr11-6394233-G-Achr11-6394233-G-Cchr11-6394233-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000543.5(SMPD1):c.1522G>A(p.Gly508Arg) variant causes a missense change. The variant allele was found at a frequency of 0.219 in 1,613,854 control chromosomes in the GnomAD database, including 40,019 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G508G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.19 (2946 hom., cov: 32)
  • Exomes 𝑓: 0.22 (37073 hom.)
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 6.33

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 Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_000543.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0019872487).
• BP6: Variant 11-6394233-G-A is Benign according to our data. Variant chr11-6394233-G-A is described in ClinVar as [Benign]. Clinvar id is 93317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6394233-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5	c.1522G>A	p.Gly508Arg	missense_variant	6/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9	c.1522G>A	p.Gly508Arg	missense_variant	6/6	1	NM_000543.5	P3

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29236 AN: 151956 Hom.: 2942 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.191

GnomAD3 exomes AF: 0.191 AC: 48098 AN: 251326 Hom.: 4926 AF XY: 0.190 AC XY: 25790 AN XY: 135832

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.137

Gnomad SAS exome AF: 0.124

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.230

Gnomad OTH exome AF: 0.191

GnomAD4 exome AF: 0.221 AC: 323546 AN: 1461780 Hom.: 37073 Cov.: 37 AF XY: 0.219 AC XY: 158913 AN XY: 727214

Gnomad4 AFR exome AF: 0.133

Gnomad4 AMR exome AF: 0.167

Gnomad4 ASJ exome AF: 0.174

Gnomad4 EAS exome AF: 0.139

Gnomad4 SAS exome AF: 0.129

Gnomad4 FIN exome AF: 0.216

Gnomad4 NFE exome AF: 0.239

Gnomad4 OTH exome AF: 0.204

GnomAD4 genome AF: 0.192 AC: 29255 AN: 152074 Hom.: 2946 Cov.: 32 AF XY: 0.189 AC XY: 14052 AN XY: 74342

Gnomad4 AFR AF: 0.139

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.180

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.121

Gnomad4 FIN AF: 0.216

Gnomad4 NFE AF: 0.233

Gnomad4 OTH AF: 0.189

Alfa AF: 0.216 Hom.: 7676

Bravo AF: 0.187

TwinsUK AF: 0.243 AC: 901

ALSPAC AF: 0.241 AC: 930

ESP6500AA AF: 0.137 AC: 604

ESP6500EA AF: 0.229 AC: 1970

ExAC AF: 0.192 AC: 23270

EpiCase AF: 0.224

EpiControl AF: 0.222

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 27, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 05, 2016	Variant Summary: The c.1522G>A in SMPD1 gene is a missense change that involves the alteration of a mildly conserved nucleotide and 3/5 in silico tools predict benign outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.19 (23261/121314 chrs tested). This frequency exceeds the maximal expected allele frequency for a pathogenic variant in this gene (0.002). A reputable database/diagnostic center has classified the variant of interest as Benign. Taking together, based on the prevalence in general population, the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24977483) -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2015	- -

Niemann-Pick disease, type A Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Niemann-Pick disease, type B Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.059	P;P;P;P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.50
Sift	Benign	0.16	T;T
Sift4G	Benign	0.17	T;T
Vest4		0.15
MPC		0.47
ClinPred		0.038	T
GERP RS		3.8
Varity_R		0.094
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1050239; hg19: chr11-6415463; COSMIC: COSV54967048; COSMIC: COSV54967048;