Variant rs775860642 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

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).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0018 ( 16 hom. )

Consequence

SMPD1
NM_000543.5 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 1.67

Variant links:

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]

SMPD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Likely_benign=1, 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	Protein	UniProt
SMPD1	NM_000543.5 linkuse as main transcript	c.107_112del	p.Val36_Leu37del	inframe_deletion	1/6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9 linkuse as main transcript	c.107_112del	p.Val36_Leu37del	inframe_deletion	1/6	1	NM_000543.5	ENSP00000340409	P3	P17405-1

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

196

AN:

139132

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00269

AC XY:

342

AN XY:

126968

show subpopulations

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.:

AF XY:

0.00188

AC XY:

1318

AN XY:

700306

show subpopulations

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.:

Cov.:

AF XY:

0.00165

AC XY:

112

AN XY:

67720

show subpopulations

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.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

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, no assertion criteria provided

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

Labcorp Genetics (formerly Invitae), Labcorp

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

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over