rs142215226

chr11-6391405-G-Achr11-6391405-G-Cchr11-6391405-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000543.5(SMPD1):c.340G>A(p.Val114Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000668 in 1,612,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00069 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00067 ( 0 hom. )

Consequence

SMPD1
NM_000543.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:18

Conservation

PhyloP100: 2.92

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.025103807).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5 linkuse as main transcript	c.340G>A	p.Val114Met	missense_variant	2/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9 linkuse as main transcript	c.340G>A	p.Val114Met	missense_variant	2/6	1	NM_000543.5	P3	P17405-1

Frequencies

GnomAD3 genomes

AF:

0.000690

AC:

105

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.00240

GnomAD3 exomes

AF:

0.000751

AC:

188

AN:

250390

Hom.:

AF XY:

0.000753

AC XY:

102

AN XY:

135464

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00107

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.000666

AC:

972

AN:

1460468

Hom.:

Cov.:

AF XY:

0.000694

AC XY:

504

AN XY:

726546

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000403

Gnomad4 ASJ exome

AF:

0.00241

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000325

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000691

Gnomad4 OTH exome

AF:

0.00116

GnomAD4 genome

AF:

0.000689

AC:

105

AN:

152294

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00101

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00110

Hom.:

Bravo

AF:

0.000778

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000931

AC:

ExAC

AF:

0.000758

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00142

EpiControl

AF:

0.00124

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Sep 22, 2023	PS3_Moderate -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 25, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 21, 2023	PM2 -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 31, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SMPD1 p.Val113Met variant was identified in the literature in one homozygote patient of six patients with hyperprolinaemia (freq: 0.167) (Reid_2017_PMID:28255779). A case study of two siblings with Niemann-Pick Disease type B also identified the V113M variant along with a H554Y variant in the SMPD1 gene; the mother carried the V113M variant and the father carried the H554Y variant (Gucev_2013_PMID:22367733). The variant was also identified in dbSNP (ID: rs142215226), ClinVar (classified as a VUS by EGL Genetics, Praxis fuer Humangenetik Tuebingen and Genomic Research Center, Shahid Beheshti University of Medical Sciences), Cosmic (FATHMM predicted pathogenic; score=0.72) and LOVD 3.0. The variant was identified in control databases in 207 of 281774 chromosomes at a frequency of 0.000735 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 32 of 10360 chromosomes (freq: 0.003089), Other in 10 of 7204 chromosomes (freq: 0.001388), European (non-Finnish) in 136 of 128262 chromosomes (freq: 0.00106), South Asian in 12 of 30614 chromosomes (freq: 0.000392), Latino in 13 of 35426 chromosomes (freq: 0.000367) and African in 4 of 24908 chromosomes (freq: 0.000161), while the variant was not observed in the East Asian and European (Finnish) populations. The p.Val113 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
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:4

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 23, 2022	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 114 of the SMPD1 protein (p.Val114Met). This variant is present in population databases (rs142215226, gnomAD 0.3%). This missense change has been observed in individual(s) with Niemann-Pick disease type B (PMID: 22367733). It has also been observed to segregate with disease in related individuals. This variant is also known as V112M. ClinVar contains an entry for this variant (Variation ID: 281705). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 01, 2021	NM_000543.4(SMPD1):c.340G>A(V114M) is a missense variant classified as a variant of uncertain significance in the context of Niemann-Pick disease, SMPD1-related. V114M has been observed in cases with relevant disease (PMID: 22367733). Functional assessments of this variant are not available in the literature. V114M has been observed in population frequency databases (gnomAD: ASJ 0.31%). In summary, there is insufficient evidence to classify NM_000543.4(SMPD1):c.340G>A(V114M) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 03, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 04, 2020	- -

Niemann-Pick disease, type A

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 22, 2023	The SMPD1 c.340G>A (p.Val114Met) variant is a missense variant. This variant has been reported in one study, in which it is found in a compound heterozygous state with another missense variant in two siblings affected with acid sphingomyelinase deficiency (PMID: 22367733). The c.340G>A variant is reported at a frequency of 0.003089 in the Ashkenazi Jewish population of the Genome Aggregation Database (version 2.1.1). This variant is located in the saposin B-like domain of SMPD1 (PMID: 27725636). Based on the available evidence, the c.340G>A (p.Val114Met) variant is classified as a variant of uncertain significance for Niemann-Pick disease, type A. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

Sphingomyelin/cholesterol lipidosis

Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Val114Met variant in SMPD1 (also known as p.Val112Met due to a difference in cDNA numbering) has been reported in at least 2 Macedonian individuals with Niemann-Pick Disease, segregated with disease in 2 affected relatives from 1 family (PMID: 22367733), and has been identified in 0.309% (32/10360) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142215226). This variant has also been reported in ClinVar (VariationID: 281705) as a VUS by EGL Genetic Diagnostics, CeGaT Praxis fuer Humangenetik Tuebingen, Shahid Beheshti University of Medical Sciences, and Illumina Clinical Services Laboratory. The Val at position 114 is not highly conserved in mammals and evolutionary distant species, and 1 mammal (Ferret) carries a Met, raising the supporting that this change at this position may be tolerated. Additional computational prediction tools do not provide strong support for or against an impact to the protein. The p.Val114Met variant is located in a region of SMPD1 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 30788890). The phenotype of an individual compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomelinase activity being less than 10% of normal consistent with disease (PMID: 22367733). In summary, the clinical significance of the p.Val114Met variant is uncertain. ACMG/AMP Criteria applied: BS1, PP4, PM3_supporting, PM1_supporting (Richards 2015). -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 02, 2019	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 07, 2023

Variant summary: SMPD1 c.340G>A (p.Val114Met) results in a conservative amino acid change located in the Saposin B type domain (IPR008139) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00075 in 250390 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SMPD1 causing Niemann-Pick Disease (0.00075 vs 0.0022), allowing no conclusion about variant significance. c.340G>A has been reported in the literature as a compound heterozygous genotype in at-least two individuals (siblings) from a family affected with an early onset form of Niemann-Pick Disease Type B (example, Gucev_2013 cited in Ota_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22367733, 31941852). Fifteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2022

The c.340G>A (p.V114M) alteration is located in exon 2 (coding exon 2) of the SMPD1 gene. This alteration results from a G to A substitution at nucleotide position 340, causing the valine (V) at amino acid position 114 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.026

BayesDel_noAF

Pathogenic

0.21

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.73

T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.025

T;T

MetaSVM

Uncertain

0.63

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.2

N;N

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0030

D;T

Sift4G

Uncertain

0.010

D;T

Vest4

0.32

MVP

0.96

MPC

0.30

ClinPred

0.059

GERP RS

3.2

Varity_R

0.23

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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