rs35098198

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000543.5(SMPD1):c.1749G>A(p.Ser583=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 1,614,050 control chromosomes in the GnomAD database, including 439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 27 hom., cov: 33)

Exomes 𝑓: 0.022 ( 412 hom. )

Consequence

SMPD1
NM_000543.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -3.39

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 11-6394460-G-A is Benign according to our data. Variant chr11-6394460-G-A is described in ClinVar as [Benign]. Clinvar id is 256593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6394460-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.39 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0169 (2571/152254) while in subpopulation NFE AF= 0.0232 (1580/68016). AF 95% confidence interval is 0.0223. There are 27 homozygotes in gnomad4. There are 1270 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMPD1	NM_000543.5 linkuse as main transcript	c.1749G>A	p.Ser583=	synonymous_variant	6/6	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.1749G>A	p.Ser583=	synonymous_variant	6/6	1	NM_000543.5	ENSP00000340409	P3	P17405-1

Frequencies

GnomAD3 genomes

AF:

0.0169

AC:

2575

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00408

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0128

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0207

Gnomad FIN

AF:

0.0392

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0232

Gnomad OTH

AF:

0.0168

GnomAD3 exomes

AF:

0.0195

AC:

4903

AN:

251302

Hom.:

AF XY:

0.0208

AC XY:

2820

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.0106

Gnomad ASJ exome

AF:

0.0191

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0206

Gnomad FIN exome

AF:

0.0397

Gnomad NFE exome

AF:

0.0236

Gnomad OTH exome

AF:

0.0218

GnomAD4 exome

AF:

0.0222

AC:

32457

AN:

1461796

Hom.:

412

Cov.:

AF XY:

0.0222

AC XY:

16145

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00343

Gnomad4 AMR exome

AF:

0.0112

Gnomad4 ASJ exome

AF:

0.0205

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0210

Gnomad4 FIN exome

AF:

0.0378

Gnomad4 NFE exome

AF:

0.0235

Gnomad4 OTH exome

AF:

0.0196

GnomAD4 genome

AF:

0.0169

AC:

2571

AN:

152254

Hom.:

Cov.:

AF XY:

0.0171

AC XY:

1270

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00407

Gnomad4 AMR

AF:

0.0127

Gnomad4 ASJ

AF:

0.0196

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0203

Gnomad4 FIN

AF:

0.0392

Gnomad4 NFE

AF:

0.0232

Gnomad4 OTH

AF:

0.0166

Alfa

AF:

0.0178

Hom.:

Bravo

AF:

0.0145

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0230

EpiControl

AF:

0.0216

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Niemann-Pick disease, type A

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 08, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.51

DANN

Benign

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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