chr11-6390705-TGCTGGCGCTGGCGCTGGC-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 2P and 17B. PM1BP3BP6_Very_StrongBA1

The NM_000543.5(SMPD1):c.126_143delGCTGGCGCTGGCGCTGGC(p.Leu43_Ala48del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 1,595,104 control chromosomes in the GnomAD database, including 237 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. A42A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.020 ( 120 hom., cov: 0)

Exomes 𝑓: 0.0025 ( 117 hom. )

Consequence

SMPD1
NM_000543.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.65

Publications

17 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 -15 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 uncertain in NM_000543.5

BP3

Nonframeshift variant in repetitive region in NM_000543.5

BP6

Variant 11-6390705-TGCTGGCGCTGGCGCTGGC-T is Benign according to our data. Variant chr11-6390705-TGCTGGCGCTGGCGCTGGC-T is described in ClinVar as Benign. ClinVar VariationId is 281329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5 link	c.126_143delGCTGGCGCTGGCGCTGGC	p.Leu43_Ala48del	disruptive_inframe_deletion	Exon 1 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.126_143delGCTGGCGCTGGCGCTGGC	p.Leu43_Ala48del	disruptive_inframe_deletion	Exon 1 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes

AF:

0.0202

AC:

2974

AN:

147220

Hom.:

120

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0697

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00627

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000399

Gnomad SAS

AF:

0.000647

Gnomad FIN

AF:

0.000296

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000728

Gnomad OTH

AF:

0.0149

GnomAD2 exomes

AF:

0.00592

AC:

1415

AN:

238972

AF XY:

0.00446

show subpopulations

Gnomad AFR exome

AF:

0.0818

Gnomad AMR exome

AF:

0.00328

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000454

Gnomad FIN exome

AF:

0.000293

Gnomad NFE exome

AF:

0.000859

Gnomad OTH exome

AF:

0.00275

GnomAD4 exome

AF:

0.00253

AC:

3656

AN:

1447758

Hom.:

117

AF XY:

0.00218

AC XY:

1569

AN XY:

720014

show subpopulations

African (AFR)

AF:

0.0719

AC:

2383

AN:

33148

American (AMR)

AF:

0.00372

AC:

165

AN:

44336

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25808

East Asian (EAS)

AF:

0.000177

AC:

AN:

39504

South Asian (SAS)

AF:

0.000726

AC:

AN:

85446

European-Finnish (FIN)

AF:

0.000212

AC:

AN:

51776

Middle Eastern (MID)

AF:

0.00316

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.000656

AC:

723

AN:

1102378

Other (OTH)

AF:

0.00481

AC:

287

AN:

59670

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

162

323

485

646

808

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

270

360

450

<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:

0.0202

AC:

2977

AN:

147346

Hom.:

120

Cov.:

AF XY:

0.0198

AC XY:

1424

AN XY:

71994

show subpopulations

African (AFR)

AF:

0.0696

AC:

2797

AN:

40208

American (AMR)

AF:

0.00632

AC:

AN:

14864

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3374

East Asian (EAS)

AF:

0.000400

AC:

AN:

5004

South Asian (SAS)

AF:

0.000646

AC:

AN:

4642

European-Finnish (FIN)

AF:

0.000296

AC:

AN:

10138

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.000728

AC:

AN:

65924

Other (OTH)

AF:

0.0147

AC:

AN:

2042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

139

279

418

558

697

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.00

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jun 05, 2018

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.126_143del18 (p.Ala44_Leu49del) results in an in-frame deletion that is predicted to remove 6 amino acids from the encoded protein. The variant allele was found at a frequency of 0.0069 in 110368 control chromosomes in the ExAC database, including 43 homozygotes. The observed variant frequency is approximately 3.071 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. To our knowledge, no occurrence of c.126_143del18 in individuals affected with Niemann-Pick Disease Type A and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

Jul 14, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

May 16, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 19, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 02, 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

Aug 09, 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

2.7

Mutation Taster

=198/2

polymorphism (auto)

(source)

Splicing

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