11-6390705-TGCTGGCGCTGGCGCTGGCGCTGGC-TGCTGGCGCTGGCGCTGGCGCTGGCGCTGGCGCTGGC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_000543.5(SMPD1):c.132_143dupGCTGGCGCTGGC(p.Ala48_Leu49insLeuAlaLeuAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A48A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

SMPD1
NM_000543.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:2

Conservation

PhyloP100: -0.158

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: Likely_benign. The variant received -1 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_000543.5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5 link	c.132_143dupGCTGGCGCTGGC	p.Ala48_Leu49insLeuAlaLeuAla	disruptive_inframe_insertion	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.132_143dupGCTGGCGCTGGC	p.Ala48_Leu49insLeuAlaLeuAla	disruptive_inframe_insertion	Exon 1 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes

AF:

0.000109

AC:

AN:

147228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000374

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000674

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000207

AC:

AN:

1447756

Hom.:

Cov.:

AF XY:

0.0000181

AC XY:

AN XY:

720014

show subpopulations

African (AFR)

AF:

0.000422

AC:

AN:

33148

American (AMR)

AF:

0.00

AC:

AN:

44336

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25808

East Asian (EAS)

AF:

0.00

AC:

AN:

39504

South Asian (SAS)

AF:

0.0000702

AC:

AN:

85446

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51776

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00000726

AC:

AN:

1102376

Other (OTH)

AF:

0.0000335

AC:

AN:

59670

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000109

AC:

AN:

147228

Hom.:

Cov.:

AF XY:

0.0000835

AC XY:

AN XY:

71866

show subpopulations

African (AFR)

AF:

0.000374

AC:

AN:

40092

American (AMR)

AF:

0.0000674

AC:

AN:

14846

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3374

East Asian (EAS)

AF:

0.00

AC:

AN:

5012

South Asian (SAS)

AF:

0.00

AC:

AN:

4640

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10138

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65934

Other (OTH)

AF:

0.00

AC:

AN:

2020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.544

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:

0.00

Hom.:

Bravo

AF:

0.000102

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Pathogenic:1Uncertain:1

Oct 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.132_143dup, results in the insertion of 4 amino acid(s) of the SMPD1 protein (p.Ala46_Leu49dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with SMPD1-related conditions (PMID: 33675270). ClinVar contains an entry for this variant (Variation ID: 992676). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Dec 30, 2020

Huiwen Zhang's lab, Shanghai Jiao Tong University School of Medicine, Xinhua Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Feb 05, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SMPD1 c.132_143dup12 (p.Ala46_Leu49dup) results in an in-frame duplication that is predicted to insert four amino acids into the (putative) signal peptide region (Rhein_2014) of the encoded protein. The variant allele was found at a frequency of 0.00011 in 146056 control chromosomes (gnomAD v3.1). However, it is located in a polymorphic region where it is in overlap with other frequent in-frame deletion-insertion variants. c.132_143dup12 has been reported in the literature as a compound heterozygous genotype in an individual affected with Niemann-Pick Disease (Hu_2021). This report does not provide unequivocal conclusions about association of the variant with Niemann-Pick Disease. A functional study analyzed the effect of variable numbers of Leu-Ala (LA) repeats in the signal peptide region, and found that variants encoding 2, 8 or 9 repeats resulted in significantly lowered ASM secretion rates compared to the wild-type with 6 LA-repeat (Rhein_2014). The following publications have been ascertained in the context of this evaluation (PMID: 33675270, 27814975, 25301364). ClinVar contains an entry for this variant (Variation ID: 992676). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Benign:1

Mar 08, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Niemann-Pick disease, type A

Benign:1

Jun 17, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.16

Mutation Taster

=82/18

disease causing (ClinVar)

(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