chr11-6390705-TGCTGGC-T

Position:

• chr11-6390705-TGCTGGC-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

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
• 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

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	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	c.138_143del	p.Ala48_Leu49del	inframe_deletion	1/6	1	NM_000543.5	P3

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

GnomAD3 exomes AF: 0.262 AC: 62584 AN: 238972 Hom.: 13465 AF XY: 0.265 AC XY: 34554 AN XY: 130606

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

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.: 0 AF XY: 0.284 AC XY: 20431 AN XY: 71944

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:1 Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign: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	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 -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 14, 2015	- -

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	Labcorp Genetics (formerly Invitae), Labcorp	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, no assertion criteria provided

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

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;