rs35824453

Variant names:

• chr11-6391952-G-A
• rs35824453
• NM_000543.5:c.887G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000543.5(SMPD1):​c.887G>A​(p.Arg296Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,614,108 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R296W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (43 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (44 hom.)
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 0.819

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

Our verdict: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000543.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.006510377).
• BP6: Variant 11-6391952-G-A is Benign according to our data. Variant chr11-6391952-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195091.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=6}. Variant chr11-6391952-G-A is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0128 (1953/152230) while in subpopulation AFR AF = 0.0449 (1863/41518). AF 95% confidence interval is 0.0432. There are 43 homozygotes in GnomAd4. There are 926 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.887G>A	p.Arg296Gln	missense_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.887G>A	p.Arg296Gln	missense_variant	Exon 2 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1953 AN: 152112 Hom.: 43 Cov.: 31

Gnomad AFR AF: 0.0450

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00911

GnomAD2 exomes AF: 0.00358 AC: 900 AN: 251438 AF XY: 0.00260

Gnomad AFR exome AF: 0.0498

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00131 AC: 1908 AN: 1461878 Hom.: 44 Cov.: 36 AF XY: 0.00109 AC XY: 796 AN XY: 727238

Gnomad4 AFR exome AF: 0.0465 AC: 1558 AN: 33478

Gnomad4 AMR exome AF: 0.00224 AC: 100 AN: 44724

Gnomad4 ASJ exome AF: 0.0000383 AC: 1 AN: 26136

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39700

Gnomad4 SAS exome AF: 0.0000464 AC: 4 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53420

Gnomad4 NFE exome AF: 0.0000612 AC: 68 AN: 1111998

Gnomad4 Remaining exome AF: 0.00277 AC: 167 AN: 60396

GnomAD4 genome AF: 0.0128 AC: 1953 AN: 152230 Hom.: 43 Cov.: 31 AF XY: 0.0124 AC XY: 926 AN XY: 74424

Gnomad4 AFR AF: 0.0449 AC: 0.0448721 AN: 0.0448721

Gnomad4 AMR AF: 0.00373 AC: 0.00372695 AN: 0.00372695

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000206 AC: 0.000205858 AN: 0.000205858

Gnomad4 OTH AF: 0.00901 AC: 0.00901328 AN: 0.00901328

Alfa AF: 0.00539 Hom.: 35

Bravo AF: 0.0147

ESP6500AA AF: 0.0452 AC: 199

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00428 AC: 520

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

May 06, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15221801, 21228398, 20981092) -

Jan 03, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 25, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SMPD1: BP4, BS1, BS2 -

not specified Benign:2

May 20, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 04, 2018

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SMPD1 c.887G>A (p.Arg296Gln) results in a conservative amino acid change located in the Calcineurin-like ApaH type phosphoesterase domain of the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0044 in 277234 control chromosomes in the gnomAD database, including 27 homozygotes. The observed variant frequency is approximately 1.96 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMPD1 causing Niemann-Pick Disease Type A phenotype (0.0022), strongly suggesting that the variant is benign. c.887G>A has been reported in the literature in individuals affected with Niemann-Pick Disease Type A. These report(s) do not provide unequivocal conclusions about association of the variant with Niemann-Pick Disease Type A. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Niemann-Pick disease, type A Benign:2

May 08, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 06, 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 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
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.21	.;T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.78	T;T;T
MetaRNN	Benign	0.0065	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.48	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.53	T;T;T
Sift4G	Benign	0.57	T;T;T
Vest4		0.13
MVP		0.89
MPC		0.25
ClinPred		0.0035	T
GERP RS		3.9
Varity_R		0.071
gMVP		0.68
Mutation Taster		=90/10	polymorphism (auto)

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: rs35824453; hg19: chr11-6413182; COSMIC: COSV54966686; COSMIC: COSV54966686;