rs35824453

Positions:

chr11-6391952-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The ENST00000342245.9(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. 14/19 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
ENST00000342245.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 0.819

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 -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, 3 uncertain in ENST00000342245.9

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: {Benign=6, Uncertain_significance=1, Likely_benign=2}. 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMPD1	NM_000543.5 linkuse as main transcript	c.887G>A	p.Arg296Gln	missense_variant	2/6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9 linkuse as main transcript	c.887G>A	p.Arg296Gln	missense_variant	2/6	1	NM_000543.5	ENSP00000340409	P3	P17405-1

Frequencies

GnomAD3 genomes

AF:

0.0128

AC:

1953

AN:

152112

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00358

AC:

900

AN:

251438

Hom.:

AF XY:

0.00260

AC XY:

354

AN XY:

135896

show subpopulations

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 SAS exome

AF:

0.0000327

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.:

Cov.:

AF XY:

0.00109

AC XY:

796

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0465

Gnomad4 AMR exome

AF:

0.00224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000612

Gnomad4 OTH exome

AF:

0.00277

GnomAD4 genome

AF:

0.0128

AC:

1953

AN:

152230

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

926

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0449

Gnomad4 AMR

AF:

0.00373

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00901

Alfa

AF:

0.00277

Hom.:

Bravo

AF:

0.0147

ESP6500AA

AF:

0.0452

AC:

199

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00428

AC:

520

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	SMPD1: BP4, BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 03, 2022	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2020	This variant is associated with the following publications: (PMID: 15221801, 21228398, 20981092) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 25, 2015	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 04, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 20, 2015	- -

Niemann-Pick disease, type A

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	- -

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

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.21

.;T;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.78

T;T;T

MetaRNN

Benign

0.0065

T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.99

N;N;N;N

PrimateAI

Benign

0.30

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

GERP RS

3.9

Varity_R

0.071

gMVP

0.68

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