Genetic Variant SMPD1:p.Val36_Leu37insAlaLeuAlaLeuAla (chr11-6390705-T-TGGCGCTGGCGCTGGC) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1BP3

The NM_000543.5(SMPD1):c.108_109insGCGCTGGCGCTGGCG(p.Val36_Leu37insAlaLeuAlaLeuAla) variant causes a conservative 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00025 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

SMPD1
NM_000543.5 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.158

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 8 uncertain in NM_000543.5

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.108_109insGCGCTGGCGCTGGCG	p.Val36_Leu37insAlaLeuAlaLeuAla	conservative_inframe_insertion	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.108_109insGCGCTGGCGCTGGCG	p.Val36_Leu37insAlaLeuAlaLeuAla	conservative_inframe_insertion	Exon 1 of 6	1	NM_000543.5	ENSP00000340409.4		P17405-1

Frequencies

GnomAD3 genomes

AF:

0.000163

AC:

AN:

147228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000674

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00129

Gnomad FIN

AF:

0.0000986

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000197

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000251

AC:

364

AN:

1447756

Hom.:

Cov.:

AF XY:

0.000307

AC XY:

221

AN XY:

720012

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33148

American (AMR)

AF:

0.000113

AC:

AN:

44336

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25808

East Asian (EAS)

AF:

0.000456

AC:

AN:

39504

South Asian (SAS)

AF:

0.00171

AC:

146

AN:

85444

European-Finnish (FIN)

AF:

0.0000966

AC:

AN:

51776

Middle Eastern (MID)

AF:

0.000351

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.000156

AC:

172

AN:

1102378

Other (OTH)

AF:

0.000268

AC:

AN:

59670

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

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:

0.000163

AC:

AN:

147354

Hom.:

Cov.:

AF XY:

0.000167

AC XY:

AN XY:

71998

show subpopulations

African (AFR)

AF:

0.0000746

AC:

AN:

40212

American (AMR)

AF:

0.0000673

AC:

AN:

14866

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3374

East Asian (EAS)

AF:

0.00

AC:

AN:

5004

South Asian (SAS)

AF:

0.00129

AC:

AN:

4642

European-Finnish (FIN)

AF:

0.0000986

AC:

AN:

10138

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.000197

AC:

AN:

65926

Other (OTH)

AF:

0.00

AC:

AN:

2042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.16

Mutation Taster

=82/18

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

Computational scores

Splicing

Publications

Other links and lift over