chr11-6391624-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000543.5(SMPD1):c.559C>T(p.Pro187Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00279 in 1,482,296 control chromosomes in the GnomAD database, including 82 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P187T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.017 ( 38 hom., cov: 31)

Exomes 𝑓: 0.0016 ( 44 hom. )

Consequence

SMPD1
NM_000543.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.759

Publications

8 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: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000543.5

BP4

Computational evidence support a benign effect (MetaRNN=0.0031031668).

BP6

Variant 11-6391624-C-T is Benign according to our data. Variant chr11-6391624-C-T is described in ClinVar as Benign. ClinVar VariationId is 195087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0559 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5 link	c.559C>T	p.Pro187Ser	missense_variant	Exon 2 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.559C>T	p.Pro187Ser	missense_variant	Exon 2 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

1875

AN:

108364

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0581

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00840

Gnomad ASJ

AF:

0.00841

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00855

Gnomad NFE

AF:

0.000447

Gnomad OTH

AF:

0.0142

GnomAD2 exomes

AF:

0.00453

AC:

635

AN:

140292

AF XY:

0.00352

show subpopulations

Gnomad AFR exome

AF:

0.0594

Gnomad AMR exome

AF:

0.00293

Gnomad ASJ exome

AF:

0.00812

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000367

Gnomad OTH exome

AF:

0.00378

GnomAD4 exome

AF:

0.00164

AC:

2257

AN:

1373882

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

1011

AN XY:

679298

show subpopulations

African (AFR)

AF:

0.0481

AC:

1501

AN:

31230

American (AMR)

AF:

0.00288

AC:

104

AN:

36164

Ashkenazi Jewish (ASJ)

AF:

0.00690

AC:

173

AN:

25058

East Asian (EAS)

AF:

0.00

AC:

AN:

35822

South Asian (SAS)

AF:

0.0000633

AC:

AN:

79004

European-Finnish (FIN)

AF:

0.0000218

AC:

AN:

45790

Middle Eastern (MID)

AF:

0.00120

AC:

AN:

4154

European-Non Finnish (NFE)

AF:

0.000235

AC:

249

AN:

1059624

Other (OTH)

AF:

0.00384

AC:

219

AN:

57036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

122

244

367

489

611

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.0173

AC:

1880

AN:

108414

Hom.:

Cov.:

AF XY:

0.0165

AC XY:

856

AN XY:

51746

show subpopulations

African (AFR)

AF:

0.0582

AC:

1734

AN:

29794

American (AMR)

AF:

0.00838

AC:

AN:

9310

Ashkenazi Jewish (ASJ)

AF:

0.00841

AC:

AN:

2736

East Asian (EAS)

AF:

0.00

AC:

AN:

3652

South Asian (SAS)

AF:

0.00

AC:

AN:

3266

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5946

Middle Eastern (MID)

AF:

0.00952

AC:

AN:

210

European-Non Finnish (NFE)

AF:

0.000447

AC:

AN:

51428

Other (OTH)

AF:

0.0141

AC:

AN:

1420

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

154

230

307

384

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00451

Hom.:

ESP6500AA

AF:

0.0448

AC:

196

ESP6500EA

AF:

0.00129

AC:

ExAC

AF:

0.00371

AC:

408

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Aug 31, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 08, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Jan 27, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 07, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The SMPD1 c.559C>T (p.Pro187Ser) variant involves the alteration of a non-conserved nucleotide and 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and Mutation Taster not captured due to low reliability index and p-value, respectively). This variant was found in 968/157662 (16 homozygotes) control chromosomes (gnomAD), predominantly observed in the African subpopulation at a frequency of 0.057086 (804/14084, 16 homozygotes)). This frequency is about 26 times the estimated maximal expected allele frequency of a pathogenic SMPD1 variant (0.0022361), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor was it evaluated for functional impact by in vivo/vitro studies. However, multiple clinical diagnostic laboratories/reputable databases classified this variant as "benign". Taken together, this variant is classified as Benign. -

Niemann-Pick disease, type A

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 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. -

Jun 14, 2017

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.16

CADD

Benign

4.9

(source)

DANN

Benign

0.95

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.77

T;T

MetaRNN

Benign

0.0031

T;T

MetaSVM

Uncertain

-0.26

PhyloP100

0.76

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-4.1

D;D

REVEL

Benign

0.21

Sift

Benign

0.077

T;T

Sift4G

Benign

0.17

T;T

Vest4

0.15

MVP

0.97

MPC

0.28

ClinPred

0.017

GERP RS

-0.45

PromoterAI

0.025

Neutral

(source)

Varity_R

0.12

gMVP

0.75

Mutation Taster

=100/0

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

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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