Variant rs7951904 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000543.5(SMPD1):c.636T>C(p.Asp212=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,561,480 control chromosomes in the GnomAD database, including 16,070 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 1602 hom., cov: 29)

Exomes 𝑓: 0.14 ( 14468 hom. )

Consequence

SMPD1
NM_000543.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.21

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=-0.64).

BP6

Variant 11-6391701-T-C is Benign according to our data. Variant chr11-6391701-T-C is described in ClinVar as [Benign]. Clinvar id is 93319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6391701-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.21 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5 linkuse as main transcript	c.636T>C	p.Asp212=	synonymous_variant	2/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9 linkuse as main transcript	c.636T>C	p.Asp212=	synonymous_variant	2/6	1	NM_000543.5	P3	P17405-1

Frequencies

GnomAD3 genomes

AF:

0.151

AC:

21308

AN:

141476

Hom.:

1599

Cov.:

show subpopulations

Gnomad AFR

AF:

0.198

Gnomad AMI

AF:

0.119

Gnomad AMR

AF:

0.127

Gnomad ASJ

AF:

0.118

Gnomad EAS

AF:

0.00254

Gnomad SAS

AF:

0.174

Gnomad FIN

AF:

0.118

Gnomad MID

AF:

0.205

Gnomad NFE

AF:

0.142

Gnomad OTH

AF:

0.150

GnomAD3 exomes

AF:

0.124

AC:

30026

AN:

243056

Hom.:

2209

AF XY:

0.127

AC XY:

16898

AN XY:

132618

show subpopulations

Gnomad AFR exome

AF:

0.190

Gnomad AMR exome

AF:

0.0771

Gnomad ASJ exome

AF:

0.129

Gnomad EAS exome

AF:

0.00407

Gnomad SAS exome

AF:

0.174

Gnomad FIN exome

AF:

0.101

Gnomad NFE exome

AF:

0.137

Gnomad OTH exome

AF:

0.143

GnomAD4 exome

AF:

0.140

AC:

198651

AN:

1419896

Hom.:

14468

Cov.:

AF XY:

0.142

AC XY:

99918

AN XY:

706106

show subpopulations

Gnomad4 AFR exome

AF:

0.194

Gnomad4 AMR exome

AF:

0.0844

Gnomad4 ASJ exome

AF:

0.137

Gnomad4 EAS exome

AF:

0.00346

Gnomad4 SAS exome

AF:

0.176

Gnomad4 FIN exome

AF:

0.112

Gnomad4 NFE exome

AF:

0.143

Gnomad4 OTH exome

AF:

0.140

GnomAD4 genome

AF:

0.151

AC:

21328

AN:

141584

Hom.:

1602

Cov.:

AF XY:

0.151

AC XY:

10274

AN XY:

68216

show subpopulations

Gnomad4 AFR

AF:

0.198

Gnomad4 AMR

AF:

0.127

Gnomad4 ASJ

AF:

0.118

Gnomad4 EAS

AF:

0.00255

Gnomad4 SAS

AF:

0.174

Gnomad4 FIN

AF:

0.118

Gnomad4 NFE

AF:

0.142

Gnomad4 OTH

AF:

0.152

Alfa

AF:

0.135

Hom.:

2096

Bravo

AF:

0.143

Asia WGS

AF:

0.0780

AC:

270

AN:

3478

EpiCase

AF:

0.142

EpiControl

AF:

0.144

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 10, 2016	Variant summary: The SMPD1 c.636T>C (p.Asp212Asp) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools predicting no significant impact on splicing and no alterations to ESE binding sites. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 14999/114470 (1/7, 1169 homozygotes), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic SMPD1 variant 1/447, suggesting this variant is likely a benign polymorphism. A reputable clinical laboratory cites the variant as "benign." Therefore, the variant of interest has been classified as Benign. -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -

Niemann-Pick disease, type A

Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 06, 2017	- -

Niemann-Pick disease, type B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.8

DANN

Benign

0.78

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