11-6390705-TGCTGGC-T

Variant names:

• chr11-6390705-TGCTGGC-T
• rs3838786
• NM_000543.5:c.138_143delGCTGGC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000543.5(SMPD1):​c.138_143delGCTGGC​(p.Leu47_Ala48del) variant causes a disruptive 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. A46A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.29 (10346 hom., cov: 0)
  • Exomes 𝑓: 0.31 (108127 hom.)
• Consequence: SMPD1 NM_000543.5 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:11
• Conservation: PhyloP100: 0.974

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.138_143delGCTGGC	p.Leu47_Ala48del	disruptive_inframe_deletion	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.138_143delGCTGGC	p.Leu47_Ala48del	disruptive_inframe_deletion	Exon 1 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes AF: 0.291 AC: 42841 AN: 147156 Hom.: 10331 Cov.: 0

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

GnomAD2 exomes AF: 0.262 AC: 62584 AN: 238972 AF XY: 0.265

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 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

Gnomad4 AFR exome AF: 0.365 AC: 12105 AN: 33136

Gnomad4 AMR exome AF: 0.167 AC: 7382 AN: 44314

Gnomad4 ASJ exome AF: 0.274 AC: 7065 AN: 25798

Gnomad4 EAS exome AF: 0.103 AC: 4068 AN: 39490

Gnomad4 SAS exome AF: 0.267 AC: 22817 AN: 85418

Gnomad4 FIN exome AF: 0.269 AC: 13924 AN: 51716

Gnomad4 NFE exome AF: 0.323 AC: 355719 AN: 1101960

Gnomad4 Remaining exome AF: 0.295 AC: 17610 AN: 59638

GnomAD4 genome AF: 0.291 AC: 42899 AN: 147282 Hom.: 10346 Cov.: 0 AF XY: 0.284 AC XY: 20431 AN XY: 71944

Gnomad4 AFR AF: 0.356 AC: 0.356133 AN: 0.356133

Gnomad4 AMR AF: 0.193 AC: 0.192893 AN: 0.192893

Gnomad4 ASJ AF: 0.261 AC: 0.260522 AN: 0.260522

Gnomad4 EAS AF: 0.0942 AC: 0.0941623 AN: 0.0941623

Gnomad4 SAS AF: 0.216 AC: 0.215517 AN: 0.215517

Gnomad4 FIN AF: 0.241 AC: 0.241121 AN: 0.241121

Gnomad4 NFE AF: 0.302 AC: 0.302051 AN: 0.302051

Gnomad4 OTH AF: 0.289 AC: 0.288725 AN: 0.288725

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.372

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:2

Sep 02, 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 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. -

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Jul 14, 2015

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:2

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 07, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Niemann-Pick disease, type A Benign:2

May 15, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SMPD1-related disorder Benign:1

Aug 05, 2022

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=192/8	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3838786; hg19: chr11-6411935; COSMIC: COSV54966198; COSMIC: COSV54966198;