Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP5

The ENST00000342245.9(SMPD1):c.592G>C(p.Ala198Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000027 in 1,405,140 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A198D) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000027 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SMPD1
ENST00000342245.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1O:1

Conservation

PhyloP100: 2.77

Publications

4 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_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in ENST00000342245.9

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-6391658-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3754296.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 11-6391657-G-C is Pathogenic according to our data. Variant chr11-6391657-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203425.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000342245.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMPD1	NM_000543.5	MANE Select	c.592G>C	p.Ala198Pro	missense	Exon 2 of 6	NP_000534.3
SMPD1	NM_001007593.3		c.589G>C	p.Ala197Pro	missense	Exon 2 of 6	NP_001007594.2
SMPD1	NM_001365135.2		c.592G>C	p.Ala198Pro	missense	Exon 2 of 5	NP_001352064.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMPD1	ENST00000342245.9	TSL:1 MANE Select	c.592G>C	p.Ala198Pro	missense	Exon 2 of 6	ENSP00000340409.4
SMPD1	ENST00000533123.5	TSL:1	n.592G>C		non_coding_transcript_exon	Exon 2 of 5	ENSP00000435950.1
SMPD1	ENST00000534405.5	TSL:1	n.592G>C		non_coding_transcript_exon	Exon 2 of 6	ENSP00000434353.1

Frequencies

GnomAD3 genomes

AF:

0.0000138

AC:

AN:

144722

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000515

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD2 exomes

AF:

0.00000490

AC:

AN:

203992

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000113

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000270

AC:

AN:

1405140

Hom.:

Cov.:

AF XY:

0.0000272

AC XY:

AN XY:

698952

show subpopulations

African (AFR)

AF:

0.0000308

AC:

AN:

32466

American (AMR)

AF:

0.00

AC:

AN:

41932

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25520

East Asian (EAS)

AF:

0.00

AC:

AN:

38268

South Asian (SAS)

AF:

0.00

AC:

AN:

83212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45988

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4530

European-Non Finnish (NFE)

AF:

0.0000335

AC:

AN:

1074888

Other (OTH)

AF:

0.0000171

AC:

AN:

58336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000138

AC:

AN:

144722

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70106

show subpopulations

African (AFR)

AF:

0.0000515

AC:

AN:

38798

American (AMR)

AF:

0.00

AC:

AN:

14134

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3404

East Asian (EAS)

AF:

0.00

AC:

AN:

4814

South Asian (SAS)

AF:

0.00

AC:

AN:

4466

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9496

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66432

Other (OTH)

AF:

0.00

AC:

AN:

1976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Niemann-Pick disease, type A (2)

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B (1)

Niemann-Pick disease, type B (1)

not provided (1)

Sphingomyelin/cholesterol lipidosis (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.014

MetaRNN

Uncertain

0.71

MetaSVM

Benign

-1.2

PhyloP100

2.8

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.11

Sift

Uncertain

0.012

Sift4G

Uncertain

0.021

Vest4

0.77

MVP

0.75

MPC

0.80

ClinPred

0.94

GERP RS

4.3

PromoterAI

-0.024

Neutral

(source)

Varity_R

0.84

gMVP

0.92

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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.

rs797044798

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over