NM_000543.5:c.636T>C

Variant names:

• chr11-6391701-T-C
• rs7951904
• NM_000543.5:c.636T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000543.5(SMPD1):​c.636T>C​(p.Asp212Asp) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.21

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=-0.64).
• 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 rank	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.636T>C	p.Asp212Asp	synonymous_variant	Exon 2 of 6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9	c.636T>C	p.Asp212Asp	synonymous_variant	Exon 2 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes AF: 0.151 AC: 21308 AN: 141476 Hom.: 1599 Cov.: 29

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

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.: 39 AF XY: 0.142 AC XY: 99918 AN XY: 706106

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.: 29 AF XY: 0.151 AC XY: 10274 AN XY: 68216

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:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 10, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Niemann-Pick disease, type A Benign:3

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 B Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Other links and lift over

dbSNP: rs7951904; hg19: chr11-6412931; COSMIC: COSV54968709; COSMIC: COSV54968709;