rs1050228

Variant names:

• chr11-6390705-T-C
• rs1050228
• NM_000543.5:c.107T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V36L) 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:12
• Conservation: PhyloP100: 1.59
• Publications: 46 publications found

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 Gene-Disease associations (from GenCC):

• acid sphingomyelinase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Niemann-Pick disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• Niemann-Pick disease type A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• Niemann-Pick disease type B

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId is 93311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.107T>C	p.Val36Ala	missense_variant	Exon 1 of 6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9	c.107T>C	p.Val36Ala	missense_variant	Exon 1 of 6	1	NM_000543.5	ENSP00000340409.4

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

GnomAD2 exomes AF: 0.554 AC: 132344 AN: 238972 AF XY: 0.552

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 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

African (AFR) AF: 0.220 AC: 7295 AN: 33142

American (AMR) AF: 0.726 AC: 32196 AN: 44324

Ashkenazi Jewish (ASJ) AF: 0.572 AC: 14759 AN: 25804

East Asian (EAS) AF: 0.790 AC: 31211 AN: 39502

South Asian (SAS) AF: 0.572 AC: 48843 AN: 85428

European-Finnish (FIN) AF: 0.557 AC: 28774 AN: 51700

Middle Eastern (MID) AF: 0.569 AC: 3239 AN: 5692

European-Non Finnish (NFE) AF: 0.503 AC: 554602 AN: 1102276

Other (OTH) AF: 0.528 AC: 31478 AN: 59658

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

African (AFR) AF: 0.254 AC: 10365 AN: 40844

American (AMR) AF: 0.662 AC: 10038 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 2069 AN: 3434

East Asian (EAS) AF: 0.789 AC: 3994 AN: 5060

South Asian (SAS) AF: 0.616 AC: 2920 AN: 4740

European-Finnish (FIN) AF: 0.565 AC: 5863 AN: 10372

Middle Eastern (MID) AF: 0.540 AC: 149 AN: 276

European-Non Finnish (NFE) AF: 0.543 AC: 36453 AN: 67076

Other (OTH) AF: 0.511 AC: 1063 AN: 2080

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:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Dec 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25811928, 26084044, 30795770) -

Sep 05, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Niemann-Pick disease, type A Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:2

Feb 01, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SMPD1-related disorder Benign:1

Feb 07, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
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
PhyloP100		1.6
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
PromoterAI		0.041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.031
gMVP		0.59
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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