rs141387770

Positions:

chr11-6391754-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP5

The NM_000543.5(SMPD1):c.689G>A(p.Arg230His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,611,926 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R230C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000066 ( 1 hom. )

Consequence

SMPD1
NM_000543.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:7

Conservation

PhyloP100: 7.40

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:

SMPD1 (HGNC:):

SMPD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a disulfide_bond (size 23) in uniprot entity ASM_HUMAN there are 16 pathogenic changes around while only 1 benign (94%) in NM_000543.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-6391753-C-T is described in Lovd as [Pathogenic].

PP5

Variant 11-6391754-G-A is Pathogenic according to our data. Variant chr11-6391754-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288072.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=6, Pathogenic=1, Likely_pathogenic=1}. Variant chr11-6391754-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMPD1	NM_000543.5 linkuse as main transcript	c.689G>A	p.Arg230His	missense_variant	2/6	ENST00000342245.9	NP_000534.3	P17405-1Q59EN6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9 linkuse as main transcript	c.689G>A	p.Arg230His	missense_variant	2/6	1	NM_000543.5	ENSP00000340409.4		P17405-1

Frequencies

GnomAD3 genomes

AF:

0.000625

AC:

AN:

151932

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000203

AC:

AN:

246700

Hom.:

AF XY:

0.000134

AC XY:

AN XY:

134074

show subpopulations

Gnomad AFR exome

AF:

0.00279

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000895

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000658

AC:

AN:

1459878

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

726382

show subpopulations

Gnomad4 AFR exome

AF:

0.00209

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000625

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.000579

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00222

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000801

Hom.:

Bravo

AF:

0.000676

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000222

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 01, 2021	NM_000543.4(SMPD1):c.689G>A(R230H) is a missense variant classified as a variant of uncertain significance in the context of Niemann-Pick disease, SMPD1-related. R230H has been observed in cases with relevant disease (PMID:15877209, 20386867, 26499107). Functional assessments of this variant are not available in the literature. Internal structural analysis of the variant is supportive of pathogenicity. R230H has been observed in population frequency databases (gnomAD: AFR 0.27%). In summary, there is insufficient evidence to classify NM_000543.4(SMPD1):c.689G>A(R230H) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 230 of the SMPD1 protein (p.Arg230His). This variant is present in population databases (rs141387770, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with ASM deficiency (PMID: 15877209, 20386867). This variant is also known as p.Arg228His. ClinVar contains an entry for this variant (Variation ID: 288072). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMPD1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg230 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17011332, 19405096, 22818240, 27338287). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Niemann-Pick disease, type A

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 02, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2024	- -

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.Arg230His variant in SMPD1 (also known as p.Arg228His due to a difference in cDNA numbering) has been reported in 3 individuals with Niemann-Pick disease (PMID: 20386867, 15877209, 26499107) and has been identified in 0.274% (67/24490) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs141387770). This variant has also been reported in ClinVar (Variation ID: 288072) as a VUS by Counsyl and EGL Genetic Diagnostics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. A pathogenic variant resulting in a different amino acid change at the same position, p.Arg230His, has been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 19405096, 17011332, 23356216, 22818240, 23252888; VariationID: 370432). The phenotype of an individual heterozygous for this variant is highly specific for Niemann-Pick disease based on reduced enzyme activity detected in an assay, consistent with disease (PMID: 15877209). This variant was reported in an unknown phase with reported pathogenic variants and in individuals with Niemann-Pick disease (PMID: 20386867, 15877209). However, this variant was also found in cis with another pathogenic variant, suggesting that it may not cause disease (PMID: 26499107). In summary, the clinical significance of the p.Arg230His variant is uncertain. ACMG/AMP Criteria applied: BS1, PM5, PP3, BP2, PP4 (Richards 2015). -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 29, 2019	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 15, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 26, 2024	PP3, PM3, PM5 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 23, 2024

Variant summary: SMPD1 c.689G>A (p.Arg230His) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type (IPR004843) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 246700 control chromosomes, predominantly at a frequency of 0.0028 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1-fold of the estimated maximal expected allele frequency for a pathogenic variant in SMPD1 causing Niemann-Pick Disease phenotype (0.0022). c.689G>A has been reported in the literature as a compound heterozygous genotype in at-least two individuals affected with Niemann Pick disease (example, Pavlu-Pereira_2005, Desnick_2010) and as a homozygous complex allele in one individual affected with Niemann Pick disease type A (Zampieri_2016). Co-occurrences with other pathogenic variant(s) have been reported (SMPD1 1805G>A, p.R602H), providing supporting evidence for a benign role (Zampieri_2016). At-least one missense at Arg230 (c.688C>T p.Arg230Cys) has been evaluated P/LP in ClinVar. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20386867, 15877209, 26499107). ClinVar contains an entry for this variant (Variation ID: 288072). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.51

MetaRNN

Uncertain

0.44

T;T

MetaSVM

Pathogenic

0.99

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-4.3

D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.78

MVP

0.98

MPC

0.89

ClinPred

0.18

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.55

gMVP

0.92

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