rs558809956

chr11-6390705-TGCTGGC-Tchr11-6390705-TGCTGGCGCTGGC-Tchr11-6390705-T-TGCTGGCGCTGGCchr11-6390705-T-TGCTGGCchr11-6390705-TGCTGGCGCTGGCGCTGGCGCTGGC-Tchr11-6390705-T-TGCTGGCGCTGGCGCTGGCchr11-6390705-TGCTGGCGCTGGCGCTGGC-Tchr11-6390705-T-TGCTGGCGCTGGCGCTGGCGCTGGCGCTGGC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000543.5(SMPD1):c.138_143del(p.Ala48_Leu49del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,594,444 control chromosomes in the GnomAD database, including 118,473 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V36V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.29 ( 10346 hom., cov: 0)

Exomes 𝑓: 0.31 ( 108127 hom. )

Consequence

SMPD1
NM_000543.5 inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:11

Conservation

PhyloP100: 0.974

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 11-6390705-TGCTGGC-T is Benign according to our data. Variant chr11-6390705-TGCTGGC-T is described in ClinVar as [Benign]. Clinvar id is 256592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6390705-TGCTGGC-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5 linkuse as main transcript	c.138_143del	p.Ala48_Leu49del	inframe_deletion	1/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9 linkuse as main transcript	c.138_143del	p.Ala48_Leu49del	inframe_deletion	1/6	1	NM_000543.5	P3	P17405-1

Frequencies

GnomAD3 genomes

AF:

0.291

AC:

42841

AN:

147156

Hom.:

10331

Cov.:

show subpopulations

Gnomad AFR

AF:

0.356

Gnomad AMI

AF:

0.412

Gnomad AMR

AF:

0.193

Gnomad ASJ

AF:

0.261

Gnomad EAS

AF:

0.0942

Gnomad SAS

AF:

0.214

Gnomad FIN

AF:

0.241

Gnomad MID

AF:

0.276

Gnomad NFE

AF:

0.302

Gnomad OTH

AF:

0.291

GnomAD3 exomes

AF:

0.262

AC:

62584

AN:

238972

Hom.:

13465

AF XY:

0.265

AC XY:

34554

AN XY:

130606

show subpopulations

Gnomad AFR exome

AF:

0.351

Gnomad AMR exome

AF:

0.154

Gnomad ASJ exome

AF:

0.277

Gnomad EAS exome

AF:

0.105

Gnomad SAS exome

AF:

0.252

Gnomad FIN exome

AF:

0.260

Gnomad NFE exome

AF:

0.311

Gnomad OTH exome

AF:

0.281

GnomAD4 exome

AF:

0.306

AC:

442170

AN:

1447162

Hom.:

108127

AF XY:

0.305

AC XY:

219484

AN XY:

719678

show subpopulations

Gnomad4 AFR exome

AF:

0.365

Gnomad4 AMR exome

AF:

0.167

Gnomad4 ASJ exome

AF:

0.274

Gnomad4 EAS exome

AF:

0.103

Gnomad4 SAS exome

AF:

0.267

Gnomad4 FIN exome

AF:

0.269

Gnomad4 NFE exome

AF:

0.323

Gnomad4 OTH exome

AF:

0.295

GnomAD4 genome

AF:

0.291

AC:

42899

AN:

147282

Hom.:

10346

Cov.:

AF XY:

0.284

AC XY:

20431

AN XY:

71944

show subpopulations

Gnomad4 AFR

AF:

0.356

Gnomad4 AMR

AF:

0.193

Gnomad4 ASJ

AF:

0.261

Gnomad4 EAS

AF:

0.0942

Gnomad4 SAS

AF:

0.216

Gnomad4 FIN

AF:

0.241

Gnomad4 NFE

AF:

0.302

Gnomad4 OTH

AF:

0.289

Bravo

AF:

0.372

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 02, 2016	Variant summary: The SMPD1 c.138_143delGCTGGC (p.Leu47_Ala48del) variant involves an in-frame deletion of 6 nucleotides located in a known repeat region. Mutation taster predicts a benign outcome for this variant. This variant was found in 24716/110368 control chromosomes (6066 homozygotes), being most prevalent in the African subpopulation with a frequency of 0.3228346 (2706/8382). This frequency greatly exceeds the estimated maximal expected allele frequency of a pathogenic SMPD1 variant (0.0022361), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. Multiple publications consider variant as a polymorphism. Considering the high frequency of the variant in the general population, it was classified as benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 14, 2015	- -
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:2

Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	African/African American population allele frequency is 34.25% (rs1050228, 7876/22434 alleles, 1698 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1 -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

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

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 07, 2022	- -

Niemann-Pick disease, type A

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 15, 2017	- -

SMPD1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2022

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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