rs550365194

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBA1

The NM_000543.5(SMPD1):c.107_118delTGCTGGCGCTGG(p.Val36_Leu39del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0753 in 1,546,630 control chromosomes in the GnomAD database, including 4,521 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V36V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.063 ( 331 hom., cov: 0)

Exomes 𝑓: 0.076 ( 4190 hom. )

Consequence

SMPD1
NM_000543.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.67

Publications

7 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 -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_000543.5

BP6

Variant 11-6390700-CCTGGTGCTGGCG-C is Benign according to our data. Variant chr11-6390700-CCTGGTGCTGGCG-C is described in ClinVar as Benign. ClinVar VariationId is 193113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5 link	c.107_118delTGCTGGCGCTGG	p.Val36_Leu39del	disruptive_inframe_deletion	Exon 1 of 6	ENST00000342245.9	NP_000534.3	P17405-1Q59EN6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9 link	c.107_118delTGCTGGCGCTGG	p.Val36_Leu39del	disruptive_inframe_deletion	Exon 1 of 6	1	NM_000543.5	ENSP00000340409.4		P17405-1

Frequencies

GnomAD3 genomes

AF:

0.0631

AC:

8772

AN:

139088

Hom.:

332

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0185

Gnomad AMI

AF:

0.0443

Gnomad AMR

AF:

0.0493

Gnomad ASJ

AF:

0.0877

Gnomad EAS

AF:

0.0680

Gnomad SAS

AF:

0.0780

Gnomad FIN

AF:

0.106

Gnomad MID

AF:

0.0971

Gnomad NFE

AF:

0.0840

Gnomad OTH

AF:

0.0717

GnomAD2 exomes

AF:

0.0703

AC:

16351

AN:

232506

AF XY:

0.0722

show subpopulations

Gnomad AFR exome

AF:

0.0149

Gnomad AMR exome

AF:

0.0367

Gnomad ASJ exome

AF:

0.0920

Gnomad EAS exome

AF:

0.0691

Gnomad FIN exome

AF:

0.0981

Gnomad NFE exome

AF:

0.0820

Gnomad OTH exome

AF:

0.0732

GnomAD4 exome

AF:

0.0765

AC:

107636

AN:

1407438

Hom.:

4190

AF XY:

0.0764

AC XY:

53525

AN XY:

700294

show subpopulations

African (AFR)

AF:

0.0144

AC:

476

AN:

33120

American (AMR)

AF:

0.0389

AC:

1675

AN:

43040

Ashkenazi Jewish (ASJ)

AF:

0.0934

AC:

2363

AN:

25308

East Asian (EAS)

AF:

0.0632

AC:

2265

AN:

35850

South Asian (SAS)

AF:

0.0678

AC:

5590

AN:

82494

European-Finnish (FIN)

AF:

0.0960

AC:

4777

AN:

49768

Middle Eastern (MID)

AF:

0.0827

AC:

464

AN:

5608

European-Non Finnish (NFE)

AF:

0.0799

AC:

85799

AN:

1074212

Other (OTH)

AF:

0.0728

AC:

4227

AN:

58038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

6084

12168

18252

24336

30420

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3134

6268

9402

12536

15670

<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:

0.0630

AC:

8773

AN:

139192

Hom.:

331

Cov.:

AF XY:

0.0630

AC XY:

4263

AN XY:

67702

show subpopulations

African (AFR)

AF:

0.0185

AC:

699

AN:

37864

American (AMR)

AF:

0.0492

AC:

704

AN:

14320

Ashkenazi Jewish (ASJ)

AF:

0.0877

AC:

295

AN:

3362

East Asian (EAS)

AF:

0.0683

AC:

328

AN:

4802

South Asian (SAS)

AF:

0.0776

AC:

315

AN:

4060

European-Finnish (FIN)

AF:

0.106

AC:

945

AN:

8948

Middle Eastern (MID)

AF:

0.102

AC:

AN:

256

European-Non Finnish (NFE)

AF:

0.0840

AC:

5290

AN:

62962

Other (OTH)

AF:

0.0730

AC:

140

AN:

1918

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

386

772

1159

1545

1931

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

106

212

318

424

530

<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:

0.0430

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 20, 2021

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SMPD1 c.107_118del12 (p.Val36_Leu39del) results in an in-frame deletion that is predicted to remove four amino acids from the encoded protein. The variant allele was found at a frequency of 0.07 in 232506 control chromosomes in the gnomAD database, including 641 homozygotes. The observed variant frequency is approximately 31.45 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMPD1 causing Niemann-Pick Disease Type A phenotype (0.0022), strongly suggesting that the variant is benign. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 22, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 24, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 02, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 01, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Niemann-Pick disease, type A

Benign:1

May 06, 2017

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.7

Mutation Taster

=198/2

polymorphism (auto)

(source)

Splicing

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