chr11-6394441-A-G

Position:

• chr11-6394441-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_000543.5(SMPD1):​c.1730A>G​(p.His577Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,614,054 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H577Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 7.13

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000543.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748
• PP5: Variant 11-6394441-A-G is Pathogenic according to our data. Variant chr11-6394441-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 550112.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5	c.1730A>G	p.His577Arg	missense_variant	6/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9	c.1730A>G	p.His577Arg	missense_variant	6/6	1	NM_000543.5	P3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 33

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: 0.00000137 AC: 2 AN: 1461888 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74334

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

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Niemann-Pick disease, type A Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 29, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2024	- -

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:2

Likely 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	Aug 16, 2022	This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 20386867, 34273913). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 577 of the SMPD1 protein (p.His577Arg). ClinVar contains an entry for this variant (Variation ID: 550112). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His577 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been observed in individuals with SMPD1-related conditions (PMID: 12712061, 20386867, 26499107), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 20386867). 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. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 03, 2022

- -

Sphingomyelin/cholesterol lipidosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Aug 28, 2023

Variant summary: SMPD1 c.1730A>G (p.His577Arg) results in a non-conservative amino acid change located in the Sphingomyelin phosphodiesterase, C-terminal domain (IPR045473) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251448 control chromosomes (gnomAD). c.1730A>G has been reported in the literature in compound heterozygous and homozygous individuals affected with Niemann-Pick Disease (Desnick_2010, Deshpande_2021). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and p.H577R had less than 1% of expressed wild-type activity (Desnick_2010). The following publications have been ascertained in the context of this evaluation (PMID: 34273913, 20386867, 27435900). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=1, likely pathogenic (n=3) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-0.31	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.80
Sift	Benign	0.27	T;T
Sift4G	Benign	0.43	T;T
Vest4		0.72
MVP		0.99
MPC		0.85
ClinPred		0.89	D
GERP RS		5.4
Varity_R		0.55
gMVP		0.80

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: rs1554935669; hg19: chr11-6415671;