11-6390705-T-TGGC

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 2P and 17B. PM1BP3BP6_Very_StrongBS1BS2

The NM_000543.5(SMPD1):c.108_109insGCG(p.Val36_Leu37insAla) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0053 ( 5 hom., cov: 0)

Exomes 𝑓: 0.0048 ( 106 hom. )

Failed GnomAD Quality Control

Consequence

SMPD1
NM_000543.5 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

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: 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 3 benign, 8 uncertain in NM_000543.5

BP3

Nonframeshift variant in repetitive region in NM_000543.5

BP6

Variant 11-6390705-T-TGGC is Benign according to our data. Variant chr11-6390705-T-TGGC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 529235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00526 (775/147350) while in subpopulation SAS AF = 0.0345 (160/4642). AF 95% confidence interval is 0.0301. There are 5 homozygotes in GnomAd4. There are 455 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5 link	c.108_109insGCG	p.Val36_Leu37insAla	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_109insGCG	p.Val36_Leu37insAla	conservative_inframe_insertion	Exon 1 of 6	1	NM_000543.5	ENSP00000340409.4		P17405-1

Frequencies

GnomAD3 genomes

AF:

0.00528

AC:

777

AN:

147224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00613

Gnomad ASJ

AF:

0.00415

Gnomad EAS

AF:

0.00878

Gnomad SAS

AF:

0.0347

Gnomad FIN

AF:

0.0179

Gnomad MID

AF:

0.0204

Gnomad NFE

AF:

0.00244

Gnomad OTH

AF:

0.00149

GnomAD2 exomes

AF:

0.00721

AC:

1724

AN:

238972

AF XY:

0.00793

show subpopulations

Gnomad AFR exome

AF:

0.00240

Gnomad AMR exome

AF:

0.00630

Gnomad ASJ exome

AF:

0.00602

Gnomad EAS exome

AF:

0.00595

Gnomad FIN exome

AF:

0.0117

Gnomad NFE exome

AF:

0.00200

Gnomad OTH exome

AF:

0.00568

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00478

AC:

6924

AN:

1447752

Hom.:

106

Cov.:

AF XY:

0.00546

AC XY:

3931

AN XY:

720008

show subpopulations

African (AFR)

AF:

0.00302

AC:

100

AN:

33146

American (AMR)

AF:

0.00701

AC:

311

AN:

44334

Ashkenazi Jewish (ASJ)

AF:

0.00527

AC:

136

AN:

25808

East Asian (EAS)

AF:

0.00694

AC:

274

AN:

39504

South Asian (SAS)

AF:

0.0294

AC:

2508

AN:

85446

European-Finnish (FIN)

AF:

0.0151

AC:

782

AN:

51776

Middle Eastern (MID)

AF:

0.00545

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00220

AC:

2428

AN:

1102376

Other (OTH)

AF:

0.00593

AC:

354

AN:

59670

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

369

739

1108

1478

1847

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

130

260

390

520

650

<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:

0.00526

AC:

775

AN:

147350

Hom.:

Cov.:

AF XY:

0.00632

AC XY:

455

AN XY:

71996

show subpopulations

African (AFR)

AF:

0.00288

AC:

116

AN:

40212

American (AMR)

AF:

0.00612

AC:

AN:

14864

Ashkenazi Jewish (ASJ)

AF:

0.00415

AC:

AN:

3374

East Asian (EAS)

AF:

0.00859

AC:

AN:

5004

South Asian (SAS)

AF:

0.0345

AC:

160

AN:

4642

European-Finnish (FIN)

AF:

0.0179

AC:

181

AN:

10136

Middle Eastern (MID)

AF:

0.0221

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.00244

AC:

161

AN:

65926

Other (OTH)

AF:

0.00147

AC:

AN:

2042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

117

156

195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 02, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

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

Oct 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Oct 13, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Niemann-Pick disease, type A

Benign:1

Aug 25, 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

-0.16

Mutation Taster

=82/18

polymorphism

(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