rs1050228

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000543.5(SMPD1):c.107T>C(p.Val36Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.489 in 149,950 control chromosomes in the GnomAD database, including 21,996 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V36RW?) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.49 ( 21996 hom., cov: 27)

Exomes 𝑓: 0.52 ( 204749 hom. )

Failed GnomAD Quality Control

Consequence

SMPD1
NM_000543.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.59

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.1145776E-6).

BP6

Variant 11-6390705-T-C is Benign according to our data. Variant chr11-6390705-T-C is described in ClinVar as [Benign]. Clinvar id is 93311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6390705-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.769 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5 link	c.107T>C	p.Val36Ala	missense_variant	Exon 1 of 6	ENST00000342245.9	NP_000534.3	P17405-1Q59EN6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9 link	c.107T>C	p.Val36Ala	missense_variant	Exon 1 of 6	1	NM_000543.5	ENSP00000340409.4		P17405-1

Frequencies

GnomAD3 genomes

AF:

0.489

AC:

73273

AN:

149830

Hom.:

21993

Cov.:

show subpopulations

Gnomad AFR

AF:

0.254

Gnomad AMI

AF:

0.421

Gnomad AMR

AF:

0.661

Gnomad ASJ

AF:

0.603

Gnomad EAS

AF:

0.789

Gnomad SAS

AF:

0.617

Gnomad FIN

AF:

0.565

Gnomad MID

AF:

0.547

Gnomad NFE

AF:

0.543

Gnomad OTH

AF:

0.509

GnomAD3 exomes

AF:

0.554

AC:

132344

AN:

238972

Hom.:

39147

AF XY:

0.552

AC XY:

72071

AN XY:

130606

show subpopulations

Gnomad AFR exome

AF:

0.216

Gnomad AMR exome

AF:

0.729

Gnomad ASJ exome

AF:

0.554

Gnomad EAS exome

AF:

0.768

Gnomad SAS exome

AF:

0.566

Gnomad FIN exome

AF:

0.541

Gnomad NFE exome

AF:

0.507

Gnomad OTH exome

AF:

0.548

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.520

AC:

752397

AN:

1447526

Hom.:

204749

Cov.:

AF XY:

0.523

AC XY:

376272

AN XY:

719874

show subpopulations

Gnomad4 AFR exome

AF:

0.220

Gnomad4 AMR exome

AF:

0.726

Gnomad4 ASJ exome

AF:

0.572

Gnomad4 EAS exome

AF:

0.790

Gnomad4 SAS exome

AF:

0.572

Gnomad4 FIN exome

AF:

0.557

Gnomad4 NFE exome

AF:

0.503

Gnomad4 OTH exome

AF:

0.528

GnomAD4 genome

AF:

0.489

AC:

73292

AN:

149950

Hom.:

21996

Cov.:

AF XY:

0.498

AC XY:

36458

AN XY:

73276

show subpopulations

Gnomad4 AFR

AF:

0.254

Gnomad4 AMR

AF:

0.662

Gnomad4 ASJ

AF:

0.603

Gnomad4 EAS

AF:

0.789

Gnomad4 SAS

AF:

0.616

Gnomad4 FIN

AF:

0.565

Gnomad4 NFE

AF:

0.543

Gnomad4 OTH

AF:

0.511

Alfa

AF:

0.503

Hom.:

2157

ESP6500AA

AF:

0.241

AC:

1052

ESP6500EA

AF:

0.565

AC:

4795

ExAC

AF:

0.542

AC:

64243

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25811928, 26084044, 30795770) -

Sep 05, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant Summary: The c.107T>C in SMPD1 gene is a missense change that involves the alteration of a non-conserved nucleotide and 4/5 in silico tools predict benign outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.6 (61590/110368 chrs tested). This frequency exceeds the maximal expected allele frequency for a pathogenic variant in this gene (0.002). A reputable database/diagnostic center has classified the variant of interest as Benign. Taking together, based on the prevalence in general population, the variant was classified as Benign. -

Niemann-Pick disease, type A

Benign:3

May 06, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:2

Feb 01, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

SMPD1-related disorder

Benign:1

Feb 07, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Niemann-Pick disease, type B

Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.75

CADD

Benign

7.8

DANN

Benign

0.61

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.29

T;T

MetaRNN

Benign

0.0000011

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.34

N;N

REVEL

Benign

0.032

Sift

Benign

0.29

T;T

Sift4G

Benign

0.58

T;T

Vest4

0.13

MPC

0.26

ClinPred

0.010

GERP RS

0.67

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.031

gMVP

0.59

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