rs141641266

Positions:

chr11-6394015-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000543.5(SMPD1):c.1460C>T(p.Ala487Val) variant causes a missense change. The variant allele was found at a frequency of 0.00437 in 1,614,168 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 28 hom. )

Consequence

SMPD1
NM_000543.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 3.75

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015504241).

BP6

Variant 11-6394015-C-T is Benign according to our data. Variant chr11-6394015-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235490.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=2, Uncertain_significance=1}. Variant chr11-6394015-C-T is described in Lovd as [Likely_benign]. Variant chr11-6394015-C-T is described in Lovd as [Pathogenic].

BS2

High Homozygotes in GnomAdExome4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMPD1	NM_000543.5 linkuse as main transcript	c.1460C>T	p.Ala487Val	missense_variant	5/6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9 linkuse as main transcript	c.1460C>T	p.Ala487Val	missense_variant	5/6	1	NM_000543.5	ENSP00000340409	P3	P17405-1

Frequencies

GnomAD3 genomes

AF:

0.00269

AC:

410

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00320

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00445

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00281

AC:

706

AN:

251474

Hom.:

AF XY:

0.00281

AC XY:

382

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00203

Gnomad FIN exome

AF:

0.00263

Gnomad NFE exome

AF:

0.00480

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00454

AC:

6642

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00449

AC XY:

3266

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00202

Gnomad4 FIN exome

AF:

0.00331

Gnomad4 NFE exome

AF:

0.00547

Gnomad4 OTH exome

AF:

0.00253

GnomAD4 genome

AF:

0.00269

AC:

410

AN:

152292

Hom.:

Cov.:

AF XY:

0.00258

AC XY:

192

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00320

Gnomad4 NFE

AF:

0.00445

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00420

Hom.:

Bravo

AF:

0.00245

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00296

AC:

359

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00507

EpiControl

AF:

0.00445

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2020	This variant is associated with the following publications: (PMID: 30548430, 28475290, 29140481, 26084044, 12369017, 23770607, 23430512) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SMPD1: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 19, 2016	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 14, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Niemann-Pick disease, type A

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 11, 2018	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 08, 2017	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 05, 2016

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.87

Eigen

Benign

0.021

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.0075

MetaRNN

Benign

0.016

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.95

D;D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Benign

2.5

N;N

REVEL

Uncertain

0.37

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Vest4

0.38

MVP

0.98

MPC

0.22

ClinPred

0.017

GERP RS

4.7

Varity_R

0.044

gMVP

0.67

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