rs267607074

chr11-6393961-A-Cchr11-6393961-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000543.5(SMPD1):c.1406A>C(p.Tyr469Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. Y469C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.88

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a strand (size 5) in uniprot entity ASM_HUMAN there are 7 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 chr11-6393961-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 992707.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 11-6393961-A-C is Pathogenic according to our data. Variant chr11-6393961-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 2996.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-6393961-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5	c.1406A>C	p.Tyr469Ser	missense_variant	5/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9	c.1406A>C	p.Tyr469Ser	missense_variant	5/6	1	NM_000543.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 11, 2022

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. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 19405096). For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with Niemann-Pick A disease and/or Niemann-Pick B disease (PMID: 19405096, 30795770). ClinVar contains an entry for this variant (Variation ID: 2996). This variant is also known as Y467S. This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 469 of the SMPD1 protein (p.Tyr469Ser). This variant is not present in population databases (gnomAD no frequency). -

Niemann-Pick disease, type A Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	28
Dann	Uncertain	0.99
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-8.1	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Vest4		0.97
MVP		0.98
MPC		0.96
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.93
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs267607074; hg19: chr11-6415191;