rs753768576

chr18-23539826-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000271.5(NPC1):c.2780C>T(p.Ala927Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,846 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A927G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: NPC1 NM_000271.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.91

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000271.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-23539826-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 2855152.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 18-23539826-G-A is Pathogenic according to our data. Variant chr18-23539826-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 552715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5	c.2780C>T	p.Ala927Val	missense_variant	18/25	ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.2780C>T	p.Ala927Val	missense_variant	18/25	1	NM_000271.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251354 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461846 Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000227

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type C1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2023	For these reasons, this variant has been classified as Pathogenic. 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: 552715). This missense change has been observed in individual(s) with Niemann-Pick type C (PMID: 11545687, 27366019, 27549128). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs753768576, gnomAD 0.01%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 927 of the NPC1 protein (p.Ala927Val). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 15, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.89	P
Vest4		0.80
MutPred		0.84		Loss of catalytic residue at A927 (P = 0.0442);
MVP		0.95
MPC		0.77
ClinPred		0.80	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs753768576; hg19: chr18-21119790; COSMIC: COSV52578701; COSMIC: COSV52578701;