11-6390606-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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). 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 NM_000543.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:3
• Conservation: PhyloP100: 0.336

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]

ACMG classification

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	UniProt
SMPD1	NM_000543.5	c.8G>A	p.Arg3His	missense_variant	1/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9	c.8G>A	p.Arg3His	missense_variant	1/6	1	NM_000543.5	P3

Frequencies

GnomAD3 genomes AF: 0.000605 AC: 92 AN: 152076 Hom.: 1 Cov.: 33

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

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

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

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:7 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 01, 2018	- -

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

Invitae

Jan 31, 2024

- -

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
MutationTaster	Benign	1.0	N;N;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

Other links and lift over

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