rs72896268

Positions:

• chr11-6392136-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001318088.2(SMPD1):​c.110C>T​(p.Pro37Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00756 in 1,614,104 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0078 (50 hom.)
• Consequence: SMPD1 NM_001318088.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.296

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 11-6392136-C-T is Benign according to our data. Variant chr11-6392136-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6392136-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.1071C>T	p.Ala357Ala	synonymous_variant	2/6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9	c.1071C>T	p.Ala357Ala	synonymous_variant	2/6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes AF: 0.00562 AC: 855 AN: 152108 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00922

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00513 AC: 1287 AN: 250744 Hom.: 9 AF XY: 0.00543 AC XY: 736 AN XY: 135608

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00370

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00216

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00807

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00777 AC: 11355 AN: 1461878 Hom.: 50 Cov.: 36 AF XY: 0.00757 AC XY: 5504 AN XY: 727242

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.00356

Gnomad4 ASJ exome AF: 0.0106

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00227

Gnomad4 FIN exome AF: 0.00112

Gnomad4 NFE exome AF: 0.00913

Gnomad4 OTH exome AF: 0.00714

GnomAD4 genome AF: 0.00562 AC: 855 AN: 152226 Hom.: 3 Cov.: 31 AF XY: 0.00516 AC XY: 384 AN XY: 74418

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.00503

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.00920

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00744 Hom.: 3

Bravo AF: 0.00566

Asia WGS AF: 0.00260 AC: 10 AN: 3478

EpiCase AF: 0.0110

EpiControl AF: 0.00919

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2021	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	SMPD1: BS2 -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 05, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 22, 2013	- -

Niemann-Pick disease, type A Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 29, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Feb 01, 2024

- -

Sphingomyelin/cholesterol lipidosis Benign:1

Likely benign, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 22, 2020

The c.1071C>T (p.Ala357=) variant in SMPD1 (also known as p.Ala355= due to a difference in cDNA numbering) has not been previously reported in individuals with Niemann-Pick disease, but has been identified in 1.062% (110/10360) of Ashkenazi Jewish chromosomes, 0.807% (1037/128468) of European (non-Finnish) chromosomes, including 9 homozygotes, and 0.378% (134/35428) of Latino chromosomes. This variant has also been reported in ClinVar (VariationID: 93310) as a VUS by Illumina Clinical Services Laboratory, as likely benign by PreventionGenetics, and as benign by Invitae, EGL Genetic Diagnostics, and Mayo Clinic Genetic Testing Laboratories. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4, BP7 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.8
DANN	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs72896268; hg19: chr11-6413366;