11-6394300-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6

The NM_000543.5(SMPD1):c.1589G>C(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. 13/21 in silico tools predict a benign 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. G530R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

SMPD1
NM_000543.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.11

Publications

3 publications found

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]

SMPD1 Gene-Disease associations (from GenCC):

acid sphingomyelinase deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Niemann-Pick disease
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
Niemann-Pick disease type A
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
Niemann-Pick disease type B
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

SMPD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 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, 4 uncertain in NM_000543.5

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 VariationId is 289948.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5 link	c.1589G>C	p.Gly530Ala	missense_variant	Exon 6 of 6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9 link	c.1589G>C	p.Gly530Ala	missense_variant	Exon 6 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes

AF:

0.00133

AC:

202

AN:

152202

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000318

AC:

AN:

251306

AF XY:

0.000199

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 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.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00532

AC:

178

AN:

33480

American (AMR)

AF:

0.000380

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111988

Other (OTH)

AF:

0.000464

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00133

AC:

202

AN:

152322

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

111

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00435

AC:

181

AN:

41584

American (AMR)

AF:

0.00111

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000218

Hom.:

Bravo

AF:

0.00160

ESP6500AA

AF:

0.00432

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000313

AC:

Asia WGS

AF:

0.000289

AC:

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

Nov 16, 2017

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, 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.

Sphingomyelin/cholesterol lipidosis

Uncertain:1

Jan 22, 2020

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

The 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 provided

Uncertain:1

May 23, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1

not specified

Benign:1

Aug 30, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SMPD1-related disorder

Benign:1

Apr 01, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This 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

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0

.;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.056

MetaRNN

Benign

0.010

T;T

MetaSVM

Uncertain

0.070

MutationAssessor

Benign

0.0

.;.

PhyloP100

2.1

PrimateAI

Benign

0.42

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

ClinPred

0.060

GERP RS

3.8

Varity_R

0.43

gMVP

0.63

Mutation Taster

=79/21

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over