Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000543.5(SMPD1):c.1328G>C(p.Arg443Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R443Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

SMPD1
NM_000543.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.67

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000543.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.924

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
SMPD1	NM_000543.5	MANE Select	c.1328G>C	p.Arg443Pro	missense	Exon 4 of 6	NP_000534.3
SMPD1	NM_001007593.3		c.1325G>C	p.Arg442Pro	missense	Exon 4 of 6	NP_001007594.2
SMPD1	NM_001365135.2		c.1196G>C	p.Arg399Pro	missense	Exon 3 of 5	NP_001352064.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMPD1	ENST00000342245.9	TSL:1 MANE Select	c.1328G>C	p.Arg443Pro	missense	Exon 4 of 6	ENSP00000340409.4
SMPD1	ENST00000526280.1	TSL:1	c.383G>C	p.Arg128Pro	missense	Exon 2 of 4	ENSP00000436278.1
SMPD1	ENST00000531303.5	TSL:1	n.*159G>C		non_coding_transcript_exon	Exon 4 of 6	ENSP00000432625.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.73

PhyloP100

2.7

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.3

REVEL

Pathogenic

0.71

Sift

Uncertain

0.011

Sift4G

Benign

0.069

Vest4

0.80

MVP

0.98

MPC

0.90

ClinPred

0.98

GERP RS

2.4

Varity_R

0.84

gMVP

0.96

Mutation Taster

=56/44

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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11-6393681-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over