NM_000543.5:c.107_130delTGCTGGCGCTGGCGCTGGCGCTGG

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3BP6_Very_StrongBS2

The NM_000543.5(SMPD1):c.107_130delTGCTGGCGCTGGCGCTGGCGCTGG(p.Val36_Leu43del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,546,828 control chromosomes in the GnomAD database, including 13 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V36V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00098 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0013 ( 13 hom. )

Consequence

SMPD1
NM_000543.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.67

Publications

2 publications found

Variant links:

COSMIC-nc: COSV54969663

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 -13 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_000543.5

BP6

Variant 11-6390700-CCTGGTGCTGGCGCTGGCGCTGGCG-C is Benign according to our data. Variant chr11-6390700-CCTGGTGCTGGCGCTGGCGCTGGCG-C is described in ClinVar as Likely_benign. ClinVar VariationId is 459633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5 link	c.107_130delTGCTGGCGCTGGCGCTGGCGCTGG	p.Val36_Leu43del	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_130delTGCTGGCGCTGGCGCTGGCGCTGG	p.Val36_Leu43del	disruptive_inframe_deletion	Exon 1 of 6	1	NM_000543.5	ENSP00000340409.4		P17405-1

Frequencies

GnomAD3 genomes

AF:

0.000970

AC:

135

AN:

139132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000909

Gnomad ASJ

AF:

0.00387

Gnomad EAS

AF:

0.000415

Gnomad SAS

AF:

0.00713

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00719

Gnomad NFE

AF:

0.00110

Gnomad OTH

AF:

0.000527

GnomAD2 exomes

AF:

0.00188

AC:

437

AN:

232506

AF XY:

0.00202

show subpopulations

Gnomad AFR exome

AF:

0.000485

Gnomad AMR exome

AF:

0.00155

Gnomad ASJ exome

AF:

0.00299

Gnomad EAS exome

AF:

0.000466

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00120

Gnomad OTH exome

AF:

0.00140

GnomAD4 exome

AF:

0.00127

AC:

1792

AN:

1407592

Hom.:

AF XY:

0.00147

AC XY:

1032

AN XY:

700352

show subpopulations

African (AFR)

AF:

0.000483

AC:

AN:

33120

American (AMR)

AF:

0.00144

AC:

AN:

43060

Ashkenazi Jewish (ASJ)

AF:

0.00383

AC:

AN:

25308

East Asian (EAS)

AF:

0.000446

AC:

AN:

35858

South Asian (SAS)

AF:

0.00713

AC:

588

AN:

82504

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49790

Middle Eastern (MID)

AF:

0.00392

AC:

AN:

5606

European-Non Finnish (NFE)

AF:

0.000822

AC:

883

AN:

1074300

Other (OTH)

AF:

0.00186

AC:

108

AN:

58046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

186

280

373

466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.000977

AC:

136

AN:

139236

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

67722

show subpopulations

African (AFR)

AF:

0.000158

AC:

AN:

37866

American (AMR)

AF:

0.000907

AC:

AN:

14326

Ashkenazi Jewish (ASJ)

AF:

0.00387

AC:

AN:

3362

East Asian (EAS)

AF:

0.000416

AC:

AN:

4804

South Asian (SAS)

AF:

0.00739

AC:

AN:

4062

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8950

Middle Eastern (MID)

AF:

0.00781

AC:

AN:

256

European-Non Finnish (NFE)

AF:

0.00110

AC:

AN:

62990

Other (OTH)

AF:

0.000521

AC:

AN:

1920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.00169

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 21, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SMPD1: PM4, BS2 -

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

PhyloP100

1.7

Mutation Taster

=198/2

polymorphism

(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