rs149939736

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PM2PM5BP4_Strong

The NM_000543.5(SMPD1):c.1675G>A(p.Val559Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000541 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 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. V559A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00055 ( 0 hom. )

Consequence

SMPD1
NM_000543.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.366

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr11-6394387-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 2498326.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.05700487).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5 linkuse as main transcript	c.1675G>A	p.Val559Ile	missense_variant	6/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9 linkuse as main transcript	c.1675G>A	p.Val559Ile	missense_variant	6/6	1	NM_000543.5	P3	P17405-1

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000485

AC:

122

AN:

251490

Hom.:

AF XY:

0.000471

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000958

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000547

AC:

800

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

400

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000684

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000480

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000982

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000794

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000738

Hom.:

Bravo

AF:

0.000487

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000651

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 06, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	- -

SMPD1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 24, 2024

The SMPD1 c.1675G>A variant is predicted to result in the amino acid substitution p.Val559Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.090% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Of note, a different variant impacting the same amino acid (p.Val559Leu) has been reported in the compound heterozygous state in a patient with sphingomyelinase deficiency and measurement of acid sphingomyelinase activity was supportive of a mild defect (Patient 18, Zhang et al. 2013. PubMed ID: 23356216). At this time, the clinical significance of the c.1675G>A (p.Val559Ile) variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Niemann-Pick disease, type A

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 17, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.94

Eigen

Benign

0.015

Eigen_PC

Benign

0.074

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.057

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.98

N;N;N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

0.26

N;N

REVEL

Benign

0.26

Sift

Benign

0.69

T;T

Sift4G

Benign

0.71

T;T

Vest4

0.14

MVP

0.93

MPC

0.26

ClinPred

0.036

GERP RS

4.9

Varity_R

0.081

gMVP

0.33

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over