rs35098198

chr11-6394460-G-Achr11-6394460-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.39

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 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5	c.1749G>A	p.Ser583=	synonymous_variant	6/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9	c.1749G>A	p.Ser583=	synonymous_variant	6/6	1	NM_000543.5	P3

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2575 AN: 152134 Hom.: 27 Cov.: 33

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.: 69 AF XY: 0.0208 AC XY: 2820 AN XY: 135842

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.: 34 AF XY: 0.0222 AC XY: 16145 AN XY: 727196

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.: 27 Cov.: 33 AF XY: 0.0171 AC XY: 1270 AN XY: 74434

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.: 13

Bravo AF: 0.0145

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0230

EpiControl AF: 0.0216

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

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	-	- -

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, no assertion criteria provided	clinical testing	Natera, Inc.	May 08, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 31, 2017	- -

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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

Other links and lift over

dbSNP: rs35098198; hg19: chr11-6415690;