rs775860642

Positions:

• chr11-6390700-CCTGGTG-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_000543.5(SMPD1):​c.107_112del​(p.Val36_Leu37del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,546,720 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L35L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0018 (16 hom.)
• Consequence: SMPD1 NM_000543.5 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• 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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 11-6390700-CCTGGTG-C is Benign according to our data. Variant chr11-6390700-CCTGGTG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 256590.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=2, Uncertain_significance=1}. Variant chr11-6390700-CCTGGTG-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5	c.107_112del	p.Val36_Leu37del	inframe_deletion	1/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9	c.107_112del	p.Val36_Leu37del	inframe_deletion	1/6	1	NM_000543.5	P3

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 196 AN: 139132 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000742

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00126

Gnomad ASJ AF: 0.000892

Gnomad EAS AF: 0.00312

Gnomad SAS AF: 0.00369

Gnomad FIN AF: 0.00168

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00211

GnomAD3 exomes AF: 0.00264 AC: 613 AN: 232506 Hom.: 17 AF XY: 0.00269 AC XY: 342 AN XY: 126968

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.000309

Gnomad EAS exome AF: 0.00332

Gnomad SAS exome AF: 0.00376

Gnomad FIN exome AF: 0.00292

Gnomad NFE exome AF: 0.00271

Gnomad OTH exome AF: 0.00193

GnomAD4 exome AF: 0.00183 AC: 2572 AN: 1407484 Hom.: 16 AF XY: 0.00188 AC XY: 1318 AN XY: 700306

Gnomad4 AFR exome AF: 0.000695

Gnomad4 AMR exome AF: 0.00209

Gnomad4 ASJ exome AF: 0.000158

Gnomad4 EAS exome AF: 0.00220

Gnomad4 SAS exome AF: 0.00371

Gnomad4 FIN exome AF: 0.00297

Gnomad4 NFE exome AF: 0.00166

Gnomad4 OTH exome AF: 0.00221

GnomAD4 genome AF: 0.00141 AC: 196 AN: 139236 Hom.: 0 Cov.: 0 AF XY: 0.00165 AC XY: 112 AN XY: 67720

Gnomad4 AFR AF: 0.000739

Gnomad4 AMR AF: 0.00126

Gnomad4 ASJ AF: 0.000892

Gnomad4 EAS AF: 0.00312

Gnomad4 SAS AF: 0.00369

Gnomad4 FIN AF: 0.00168

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.00208

Alfa AF: 0.00178 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SMPD1: PM4, BS2 -

Sphingomyelin/cholesterol lipidosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Mar 08, 2022

Variant summary: SMPD1 c.107_112delTGCTGG (p.Val36_Leu37del) results in an in-frame deletion that is predicted to remove two amino acids from the encoded protein. The variant allele was found at a frequency of 0.0026 in 232506 control chromosomes, predominantly at a frequency of 0.0038 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMPD1 causing Niemann-Pick Disease phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two classified as benign/likely benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as benign. -

SMPD1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 15, 2021

This variant is classified as likely 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Niemann-Pick disease, type A Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 10, 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: rs775860642; hg19: chr11-6411930;