rs1190383931

chr18-23554785-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000271.5(NPC1):c.1526A>C(p.Tyr509Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,776 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).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: NPC1 NM_000271.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.88

Genes affected

NPC1 (HGNC:7897): (NPC intracellular cholesterol transporter 1) This gene encodes a large protein that resides in the limiting membrane of endosomes and lysosomes and mediates intracellular cholesterol trafficking via binding of cholesterol to its N-terminal domain. It is predicted to have a cytoplasmic C-terminus, 13 transmembrane domains, and 3 large loops in the lumen of the endosome - the last loop being at the N-terminus. This protein transports low-density lipoproteins to late endosomal/lysosomal compartments where they are hydrolized and released as free cholesterol. Defects in this gene cause Niemann-Pick type C disease, a rare autosomal recessive neurodegenerative disorder characterized by over accumulation of cholesterol and glycosphingolipids in late endosomal/lysosomal compartments.[provided by RefSeq, Aug 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 4 uncertain in NM_000271.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 18-23554785-T-G is Pathogenic according to our data. Variant chr18-23554785-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 554002.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5	c.1526A>C	p.Tyr509Ser	missense_variant	9/25	ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.1526A>C	p.Tyr509Ser	missense_variant	9/25	1	NM_000271.5	P1
NPC1	ENST00000591051.1	c.809A>C	p.Tyr270Ser	missense_variant	4/18	2
NPC1	ENST00000540608.5	n.1440A>C		non_coding_transcript_exon_variant	7/16	2
NPC1	ENST00000590301.1	n.201A>C		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461776 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727204

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: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Niemann-Pick disease, type C1 Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 04, 2023	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr509 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been observed in individuals with NPC1-related conditions (PMID: 22676771), which suggests that this may be a clinically significant amino acid residue. 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 NPC1 protein function. ClinVar contains an entry for this variant (Variation ID: 554002). This missense change has been observed in individuals with Niemann-Pick disease type C (PMID: 26666848, 30202070; Invitae). It has also been observed to segregate with disease in related individuals. This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 509 of the NPC1 protein (p.Tyr509Ser). -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 22, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	0.65	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.73	P
Vest4		0.79
MutPred		0.86		Loss of sheet (P = 0.0315);
MVP		0.91
MPC		0.98
ClinPred		0.99	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.95

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: rs1190383931; hg19: chr18-21134749;