chr11-6390606-G-A

Position:

chr11-6390606-G-A

Variant summary

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

The ENST00000342245.9(SMPD1):c.8G>A(p.Arg3His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000984 in 1,612,216 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R3R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00060 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 0 hom. )

Consequence

SMPD1
ENST00000342245.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:3

Conservation

PhyloP100: 0.336

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=0.0068249106).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMPD1	NM_000543.5 linkuse as main transcript	c.8G>A	p.Arg3His	missense_variant	1/6	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.8G>A	p.Arg3His	missense_variant	1/6	1	NM_000543.5	ENSP00000340409	P3	P17405-1

Frequencies

GnomAD3 genomes

AF:

0.000605

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00116

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000594

AC:

144

AN:

242350

Hom.:

AF XY:

0.000595

AC XY:

AN XY:

132862

show subpopulations

Gnomad AFR exome

AF:

0.000350

Gnomad AMR exome

AF:

0.000263

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000480

Gnomad NFE exome

AF:

0.00115

Gnomad OTH exome

AF:

0.000676

GnomAD4 exome

AF:

0.00102

AC:

1495

AN:

1460022

Hom.:

Cov.:

AF XY:

0.000966

AC XY:

702

AN XY:

726352

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.0000767

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000134

Gnomad4 NFE exome

AF:

0.00127

Gnomad4 OTH exome

AF:

0.000945

GnomAD4 genome

AF:

0.000604

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00116

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000943

Hom.:

Bravo

AF:

0.000642

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00106

AC:

ExAC

AF:

0.000579

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.000952

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2022	Identified in the heterozygous state in a patient with intellectual disability, short stature, microcephaly, and dysmorphic features who has other variants that may explain the phenotype (Qiao et al., 2017); Identified in the heterozygous state in a patient with a suspected lysosomal storage disease; however, a second variant was not reported (Fernandez-Marmiesse et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24767253, 28475290) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 21, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Niemann-Pick disease, type A

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 27, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 01, 2018	- -
Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

SMPD1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 17, 2023

The SMPD1 c.8G>A variant is predicted to result in the amino acid substitution p.Arg3His. This variant has been reported in the heterozygous state in an individual with a lysosomal storage disorder, however no additional evidence was provided to support the pathogenicity of this variant (see Table 5 in Fernández-Marmiesse et al. 2014. PubMed ID: 24767253). This variant is reported in 0.11% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-6411836-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Sphingomyelin/cholesterol lipidosis

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

May 05, 2017

- -

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

Benign:1

Likely 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

0.084

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.65

CADD

Benign

8.7

DANN

Benign

0.97

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.51

T;T

M_CAP

Benign

0.0042

MetaRNN

Benign

0.0068

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.55

N;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

0.090

N;N

REVEL

Benign

0.016

Sift

Benign

0.32

T;T

Sift4G

Benign

0.21

T;T

Vest4

0.095

MVP

0.30

MPC

0.26

ClinPred

0.012

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.030

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