rs1050228

chr11-6390705-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BA1

The NM_000543.5(SMPD1):c.107T>C(p.Val36Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.489 in 149,950 control chromosomes in the GnomAD database, including 21,996 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V36ALALA) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.49 (21996 hom., cov: 27)
  • Exomes 𝑓: 0.52 (204749 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.59

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 Benign. Variant got -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-6390704-GT-CGCTGGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2503937.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=1.1145776E-6).
• BP6: Variant 11-6390705-T-C is Benign according to our data. Variant chr11-6390705-T-C is described in ClinVar as [Benign]. Clinvar id is 93311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6390705-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.769 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5	c.107T>C	p.Val36Ala	missense_variant	1/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9	c.107T>C	p.Val36Ala	missense_variant	1/6	1	NM_000543.5	P3

Frequencies

GnomAD3 genomes AF: 0.489 AC: 73273 AN: 149830 Hom.: 21993 Cov.: 27

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.661

Gnomad ASJ AF: 0.603

Gnomad EAS AF: 0.789

Gnomad SAS AF: 0.617

Gnomad FIN AF: 0.565

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.509

GnomAD3 exomes AF: 0.554 AC: 132344 AN: 238972 Hom.: 39147 AF XY: 0.552 AC XY: 72071 AN XY: 130606

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.729

Gnomad ASJ exome AF: 0.554

Gnomad EAS exome AF: 0.768

Gnomad SAS exome AF: 0.566

Gnomad FIN exome AF: 0.541

Gnomad NFE exome AF: 0.507

Gnomad OTH exome AF: 0.548

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.520 AC: 752397 AN: 1447526 Hom.: 204749 Cov.: 70 AF XY: 0.523 AC XY: 376272 AN XY: 719874

Gnomad4 AFR exome AF: 0.220

Gnomad4 AMR exome AF: 0.726

Gnomad4 ASJ exome AF: 0.572

Gnomad4 EAS exome AF: 0.790

Gnomad4 SAS exome AF: 0.572

Gnomad4 FIN exome AF: 0.557

Gnomad4 NFE exome AF: 0.503

Gnomad4 OTH exome AF: 0.528

GnomAD4 genome AF: 0.489 AC: 73292 AN: 149950 Hom.: 21996 Cov.: 27 AF XY: 0.498 AC XY: 36458 AN XY: 73276

Gnomad4 AFR AF: 0.254

Gnomad4 AMR AF: 0.662

Gnomad4 ASJ AF: 0.603

Gnomad4 EAS AF: 0.789

Gnomad4 SAS AF: 0.616

Gnomad4 FIN AF: 0.565

Gnomad4 NFE AF: 0.543

Gnomad4 OTH AF: 0.511

Alfa AF: 0.503 Hom.: 2157

ESP6500AA AF: 0.241 AC: 1052

ESP6500EA AF: 0.565 AC: 4795

ExAC AF: 0.542 AC: 64243

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 05, 2016	Variant Summary: The c.107T>C in SMPD1 gene is a missense change that involves the alteration of a non-conserved nucleotide and 4/5 in silico tools predict benign outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.6 (61590/110368 chrs tested). This frequency exceeds the maximal expected allele frequency for a pathogenic variant in this gene (0.002). A reputable database/diagnostic center has classified the variant of interest as Benign. Taking together, based on the prevalence in general population, the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2018	This variant is associated with the following publications: (PMID: 25811928, 26084044, 30795770) -

Niemann-Pick disease, type A Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 01, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

Niemann-Pick disease, type B Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

SMPD1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	7.8
Dann	Benign	0.61
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.29	T;T
MetaRNN	Benign	0.0000011	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.34	N;N
REVEL	Benign	0.032
Sift	Benign	0.29	T;T
Sift4G	Benign	0.58	T;T
Vest4		0.13
MPC		0.26
ClinPred		0.010	T
GERP RS		0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.031
gMVP		0.59

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: rs1050228; hg19: chr11-6411935; COSMIC: COSV54967594; COSMIC: COSV54967594;