Genetic Variant SMPD1:p.Arg498Leu (chr11-6394204-G-T) – ACMG Classification: Pathogenic (20 pts)

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000543.5(SMPD1):c.1493G>T(p.Arg498Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000494246: an in vitro functional assay demonstrated that this variant resulted in reduced enzymatic activity, and mice with this variant also demonstrate very low SMPD1 enzymatic activity in the brain (Jones et al., 2008)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R498C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

SMPD1
NM_000543.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16O:1

Conservation

PhyloP100: 9.37

Publications

35 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: Orphanet, Genomics England PanelApp, PanelApp Australia, G2P
Niemann-Pick disease type B
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, 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: Pathogenic. The variant received 20 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000494246: an in vitro functional assay demonstrated that this variant resulted in reduced enzymatic activity, and mice with this variant also demonstrate very low SMPD1 enzymatic activity in the brain (Jones et al., 2008).; SCV000697412: supported by a functional study, Levran_1992.; SCV001422557: "In vitro functional studies provide additional evidence that the p.Arg498Leu variant may impact protein function (PMID: 18815062)."; SCV000490819: Functional studies found R498L is associated with less than 2% of wild-type enzyme activity (Jones et al., 2008);; SCV000631412: Experimental studies have shown that this missense change affects SMPD1 function (PMID: 1391960, 18815062).; SCV004954300: Functional studies demonstrated reduced enzymatic activity in patient fibroblasts and transgenic mice with this mutation (Jones, 2008).; SCV005356426: In vitro, in situ, and in vivo experimental studies indicate that this variant almost completely abolishes the enzyme activity of the SMPD1 protein (referred to as R496L, Jones et al 2008. PubMed ID: 18815062).

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000543.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-6394203-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 198095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.881

PP5

Variant 11-6394204-G-T is Pathogenic according to our data. Variant chr11-6394204-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000543.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMPD1	NM_000543.5	MANE Select	c.1493G>T	p.Arg498Leu	missense	Exon 6 of 6	NP_000534.3
SMPD1	NM_001007593.3		c.1490G>T	p.Arg497Leu	missense	Exon 6 of 6	NP_001007594.2	P17405-4
SMPD1	NM_001365135.2		c.1361G>T	p.Arg454Leu	missense	Exon 5 of 5	NP_001352064.1	P17405-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMPD1	ENST00000342245.9	TSL:1 MANE Select	c.1493G>T	p.Arg498Leu	missense	Exon 6 of 6	ENSP00000340409.4	P17405-1
SMPD1	ENST00000526280.1	TSL:1	c.548G>T	p.Arg183Leu	missense	Exon 4 of 4	ENSP00000436278.1	H0YEP5
SMPD1	ENST00000531303.5	TSL:1	n.*344G>T		non_coding_transcript_exon	Exon 6 of 6	ENSP00000432625.1	E9PPK6

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000961

GnomAD2 exomes

AF:

0.000135

AC:

AN:

251078

AF XY:

0.000140

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000534

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00233

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1112012

Other (OTH)

AF:

0.000116

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

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:

0.0000920

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68016

Other (OTH)

AF:

0.000961

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.0000561

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Niemann-Pick disease, type A (5)

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B (3)

not provided (3)

Sphingomyelin/cholesterol lipidosis (3)

Inborn genetic diseases (1)

Niemann-Pick disease, type B (1)

SMPD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.43

PhyloP100

9.4

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-6.4

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Vest4

0.98

MVP

0.98

MPC

0.85

ClinPred

0.98

GERP RS

4.7

Varity_R

0.88

gMVP

0.97

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.28

Position offset: 15

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over