11-6393620-C-T

Position:

chr11-6393620-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000543.5(SMPD1):c.1267C>T(p.His423Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,611,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H423R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SMPD1
NM_000543.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 7.13

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 Pathogenic. Variant got 16 ACMG points.

PM1

In a disulfide_bond (size 46) in uniprot entity ASM_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_000543.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.91

PP5

Variant 11-6393620-C-T is Pathogenic according to our data. Variant chr11-6393620-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6393620-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMPD1	NM_000543.5 link	c.1267C>T	p.His423Tyr	missense_variant	4/6	ENST00000342245.9	NP_000534.3	P17405-1Q59EN6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9 link	c.1267C>T	p.His423Tyr	missense_variant	4/6	1	NM_000543.5	ENSP00000340409.4		P17405-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1459646

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726300

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type A

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Dec 07, 2021	A Heterozygous missense variation in exon 4 of the SMPD1 gene that results in the amino acid substitution of Tyrosine for Histidine at codon 423 was detected. The observed variant c.1267C>T (p.His423Tyr) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are possibly damaging by DANN, FATHMM, PROVEAN. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	Enzyme deficiency -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 21, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -

Niemann-Pick disease, type B

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 01, 2020	Variant summary: SMPD1 c.1267C>T (p.His423Tyr) results in a conservative amino acid change located in the Acid sphingomyelinase/endophosphatase, metallophosphatase domain (IPR041805) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 249054 control chromosomes. c.1267C>T has been reported in the literature in multiple individuals affected with Niemann-Pick Disease (example, Fotoulaki_2007, Simonaro_2002) and has been cited by as one of the most common type B NPD allele among the Saudi population. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in both in-vitro and in-situ enzyme assays (Jones_2008). Four 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 pathogenic (n=3)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	Enzyme deficiency -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Oct 26, 2016	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 09, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2019	Published functional studies demonstrate a damaging effect (Jones et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33101984, 32292456, 26981555, 26499107, 27338287, 28600779, 17876723, 20301544, 12369017, 18815062) -

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

Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS	Apr 25, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 423 of the SMPD1 protein (p.His423Tyr). This variant is present in population databases (rs120074126, gnomAD 0.0009%). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 12369017, 17876723, 27338287, 28600779). This variant is also known as p.His421Tyr. ClinVar contains an entry for this variant (Variation ID: 2992). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMPD1 protein function with a positive predictive value of 95%. This variant disrupts the p.His423 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been observed in individuals with SMPD1-related conditions (PMID: 16434659), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Sphingomyelin/cholesterol lipidosis

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	Found most commonly in persons from Saudi Arabia. Leads to early-onset severe form of Niemann-Pick disease type-A -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.His423Tyr variant in SMPD1 (also known as p.His421Tyr due to a difference in cDNA numbering) has been reported in at least 13 individuals with Niemann-Pick disease (PMID: 12369017, 27338287, 26981555, 17876723) and has been identified in 0.002% (1/66538) of European (non-Finnish) chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs120074126). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 2992) as likely pathogenic by Invitae and as pathogenic by Counsyl, EGL Genetic Diagnostics, OMIM and GeneReviews. In vitro functional studies provide some evidence that the p.His423Tyr variant may impact protein function (PMID: 18815062). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in at least 12 affected homozygotes and with another pathogenic variant in an affected individual increases the likelihood that the p.His423 variant is pathogenic (VariationID: 188840; PMID: 12369017, 27338287, 26981555, 17876723). The phenotype of an individual homozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal, consistent with disease (PMID: 27338287, 17876723). The p.His423Tyr variant is located in a region of SMPD1 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 12369017, 18815062). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on functional studies, its location in an active site and zinc binding site, its presence in affected homozygotes, and its presence in patients with a phenotype highly specific for disease. ACMG/AMP Criteria applied: PS3, PM2, PM1, PM3, PP3, PP4 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.082

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.15

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.9

D;D

REVEL

Pathogenic

0.82

Sift

Benign

0.058

T;T

Sift4G

Benign

0.13

T;T

Vest4

0.93

MVP

0.96

MPC

0.71

ClinPred

0.98

GERP RS

4.8

Varity_R

0.81

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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