rs751269562

Positions:

• chr11-6390912-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000543.5(SMPD1):​c.314T>C​(p.Leu105Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,836 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L105L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.97

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 14 ACMG points.

• PM1: In a helix (size 15) in uniprot entity ASM_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000543.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 11-6390912-T-C is Pathogenic according to our data. Variant chr11-6390912-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6390912-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5	c.314T>C	p.Leu105Pro	missense_variant	1/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9	c.314T>C	p.Leu105Pro	missense_variant	1/6	1	NM_000543.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249832 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135396

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461836 Hom.: 0 Cov.: 38 AF XY: 0.00000413 AC XY: 3 AN XY: 727214

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 01, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 16010684, 34273913). 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. ClinVar contains an entry for this variant (Variation ID: 556092). This variant is also known as c.308T>C (p.L103P). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 15221801, 22818240, 33083013, 34273913). This variant is present in population databases (rs751269562, gnomAD 0.0009%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 105 of the SMPD1 protein (p.Leu105Pro). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 14, 2022	- -

Niemann-Pick disease, type A Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 11, 2018	- -
Pathogenic, criteria provided, single submitter	research	Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS	Apr 25, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.68	T;T
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Pathogenic	0.88
Sift	Uncertain	0.010	D;T
Sift4G	Uncertain	0.0070	D;T
Vest4		0.96
MVP		0.98
MPC		1.0
ClinPred		0.92	D
GERP RS		5.3
Varity_R		0.92
gMVP		0.96

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: rs751269562; hg19: chr11-6412142;