NM_000543.5:c.107_112delTGCTGG

Variant names:

• chr11-6390700-CCTGGTG-C
• rs775860642
• NM_000543.5:c.107_112delTGCTGG

Variant summary

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

The NM_000543.5(SMPD1):​c.107_112delTGCTGG​(p.Val36_Leu37del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 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).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0018 (16 hom.)
• Consequence: SMPD1 NM_000543.5 disruptive_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: {Uncertain_significance=1, Benign=2, Likely_benign=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 rank	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.107_112delTGCTGG	p.Val36_Leu37del	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.107_112delTGCTGG	p.Val36_Leu37del	disruptive_inframe_deletion	Exon 1 of 6	1	NM_000543.5	ENSP00000340409.4

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

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SMPD1: PM4, BS2 -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sphingomyelin/cholesterol lipidosis Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 08, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 15, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Niemann-Pick disease, type A Benign:1

Aug 10, 2017

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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;