rs550365194

chr11-6390700-CCTGGTGCTGGCG-Cchr11-6390700-CCTGGTGCTGGCG-CCTGGTGCTGGCGCTGGTGCTGGCG

Variant summary

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

The NM_000543.5(SMPD1):c.107_118del(p.Val36_Leu39del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0753 in 1,546,630 control chromosomes in the GnomAD database, including 4,521 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L35L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.063 (331 hom., cov: 0)
  • Exomes 𝑓: 0.076 (4190 hom.)
• Consequence: SMPD1 NM_000543.5 inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.67

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 11-6390700-CCTGGTGCTGGCG-C is Benign according to our data. Variant chr11-6390700-CCTGGTGCTGGCG-C is described in ClinVar as [Benign]. Clinvar id is 193113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6390700-CCTGGTGCTGGCG-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5	c.107_118del	p.Val36_Leu39del	inframe_deletion	1/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9	c.107_118del	p.Val36_Leu39del	inframe_deletion	1/6	1	NM_000543.5	P3

Frequencies

GnomAD3 genomes AF: 0.0631 AC: 8772 AN: 139088 Hom.: 332 Cov.: 0

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.0443

Gnomad AMR AF: 0.0493

Gnomad ASJ AF: 0.0877

Gnomad EAS AF: 0.0680

Gnomad SAS AF: 0.0780

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.0971

Gnomad NFE AF: 0.0840

Gnomad OTH AF: 0.0717

GnomAD3 exomes AF: 0.0703 AC: 16351 AN: 232506 Hom.: 641 AF XY: 0.0722 AC XY: 9169 AN XY: 126968

Gnomad AFR exome AF: 0.0149

Gnomad AMR exome AF: 0.0367

Gnomad ASJ exome AF: 0.0920

Gnomad EAS exome AF: 0.0691

Gnomad SAS exome AF: 0.0693

Gnomad FIN exome AF: 0.0981

Gnomad NFE exome AF: 0.0820

Gnomad OTH exome AF: 0.0732

GnomAD4 exome AF: 0.0765 AC: 107636 AN: 1407438 Hom.: 4190 AF XY: 0.0764 AC XY: 53525 AN XY: 700294

Gnomad4 AFR exome AF: 0.0144

Gnomad4 AMR exome AF: 0.0389

Gnomad4 ASJ exome AF: 0.0934

Gnomad4 EAS exome AF: 0.0632

Gnomad4 SAS exome AF: 0.0678

Gnomad4 FIN exome AF: 0.0960

Gnomad4 NFE exome AF: 0.0799

Gnomad4 OTH exome AF: 0.0728

GnomAD4 genome AF: 0.0630 AC: 8773 AN: 139192 Hom.: 331 Cov.: 0 AF XY: 0.0630 AC XY: 4263 AN XY: 67702

Gnomad4 AFR AF: 0.0185

Gnomad4 AMR AF: 0.0492

Gnomad4 ASJ AF: 0.0877

Gnomad4 EAS AF: 0.0683

Gnomad4 SAS AF: 0.0776

Gnomad4 FIN AF: 0.106

Gnomad4 NFE AF: 0.0840

Gnomad4 OTH AF: 0.0730

Alfa AF: 0.0430 Hom.: 38

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 20, 2021	Variant summary: SMPD1 c.107_118del12 (p.Val36_Leu39del) results in an in-frame deletion that is predicted to remove four amino acids from the encoded protein. The variant allele was found at a frequency of 0.07 in 232506 control chromosomes in the gnomAD database, including 641 homozygotes. The observed variant frequency is approximately 31.45 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMPD1 causing Niemann-Pick Disease Type A phenotype (0.0022), strongly suggesting that the variant is benign. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 24, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 22, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Niemann-Pick disease, type A Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

May 06, 2017

- -

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: rs550365194; hg19: chr11-6411930;