chr11-6390606-G-A

Variant summary

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

The NM_000543.5(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).

Frequency

Genomes: 𝑓 0.00060 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0010 ( 0 hom. )

Consequence

SMPD1
NM_000543.5 missense

Scores

19

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]

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 rank MANE Protein UniProt
SMPD1NM_000543.5 linkc.8G>A p.Arg3His 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
SMPD1ENST00000342245.9 linkc.8G>A p.Arg3His missense_variant Exon 1 of 6 1 NM_000543.5 ENSP00000340409.4 P17405-1

Frequencies

GnomAD3 genomes
AF:
0.000605
AC:
92
AN:
152076
Hom.:
1
Cov.:
33
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.:
0
AF XY:
0.000595
AC XY:
79
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.:
0
Cov.:
30
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:
92
AN:
152194
Hom.:
1
Cov.:
33
AF XY:
0.000497
AC XY:
37
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.:
1
Bravo
AF:
0.000642
TwinsUK
AF:
0.00162
AC:
6
ALSPAC
AF:
0.00156
AC:
6
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00106
AC:
9
ExAC
AF:
0.000579
AC:
70
Asia WGS
AF:
0.000289
AC:
1
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
Dec 12, 2022
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Dec 21, 2017
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Niemann-Pick disease, type A Uncertain:3
Jun 01, 2018
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Aug 27, 2020
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

SMPD1-related disorder Uncertain:1
Aug 17, 2023
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
May 05, 2017
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Benign:1
Dec 09, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.084
BayesDel_addAF
Benign
-0.59
T
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
N
LIST_S2
Benign
0.51
T;T
M_CAP
Benign
0.0042
T
MetaRNN
Benign
0.0068
T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.55
N;N
PrimateAI
Benign
0.32
T
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
T
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.

Other links and lift over

dbSNP: rs199836262; hg19: chr11-6411836; COSMIC: COSV54968081; COSMIC: COSV54968081; API