rs1181604094

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000271.5(NPC1):c.2597T>C(p.Met866Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,740 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NPC1
NM_000271.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.09

Variant links:

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]

NPC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a topological_domain Lumenal (size 243) in uniprot entity NPC1_HUMAN there are 84 pathogenic changes around while only 9 benign (90%) in NM_000271.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5 link	c.2597T>C	p.Met866Thr	missense_variant	Exon 17 of 25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPC1	ENST00000269228.10 link	c.2597T>C	p.Met866Thr	missense_variant	Exon 17 of 25	1	NM_000271.5	ENSP00000269228.4	O15118-1
NPC1	ENST00000591051.1 link	c.1673T>C	p.Met558Thr	missense_variant	Exon 10 of 18	2		ENSP00000467636.1	K7EQ23
NPC1	ENST00000540608.5 link	n.2511T>C		non_coding_transcript_exon_variant	Exon 15 of 16	2
NPC1	ENST00000586718.1 link	n.388T>C		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249142

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134688

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1444740

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719526

show subpopulations

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:

9.11e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	3billion, Medical Genetics	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.85; 3Cnet: 0.92). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with NPC1 related disorder (PMID: 26981555). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 24, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.94

MutPred

0.66

Loss of stability (P = 0.0361);

MVP

0.96

MPC

0.58

ClinPred

0.98

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over