18-23539393-C-T

Position:

chr18-23539393-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The ENST00000269228.10(NPC1):c.2873G>A(p.Arg958Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,842 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R958L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

NPC1
ENST00000269228.10 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 7.75

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 9 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in ENST00000269228.10

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.931

PP5

Variant 18-23539393-C-T is Pathogenic according to our data. Variant chr18-23539393-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2968.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1	NM_000271.5 linkuse as main transcript	c.2873G>A	p.Arg958Gln	missense_variant	19/25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10 linkuse as main transcript	c.2873G>A	p.Arg958Gln	missense_variant	19/25	1	NM_000271.5	ENSP00000269228	P1	O15118-1
NPC1	ENST00000591051.1 linkuse as main transcript	c.1952G>A	p.Arg651Gln	missense_variant	12/18	2		ENSP00000467636
NPC1	ENST00000591075.1 linkuse as main transcript	n.506G>A		non_coding_transcript_exon_variant	1/3	4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251178

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

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:

0.00000616

AC:

AN:

1461644

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000193

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 958 of the NPC1 protein (p.Arg958Gln). This variant is present in population databases (rs120074132, gnomAD 0.006%). This missense change has been observed in individual(s) with Niemann-Pick disease type C (PMID: 11349231). ClinVar contains an entry for this variant (Variation ID: 2968). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg958 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been observed in individuals with NPC1-related conditions (PMID: 11754101, 35086560), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 16, 2021	NM_000271.4(NPC1):c.2873G>A(R958Q) is a missense variant classified as a variant of uncertain significance in the context of Niemann-Pick disease type C1. R958Q has been observed in cases with relevant disease (PMID: 11349231, 17160617, 23433426). Functional assessments of this variant are available in the literature (PMID: 28193631, 31699992). R958Q has been observed in population frequency databases (gnomAD: EAS 0.01%). In summary, there is insufficient evidence to classify NM_000271.4(NPC1):c.2873G>A(R958Q) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Aug 08, 2022	A compound heterozygous missense variation in exon 19 of the NPC1 gene that results in the amino acid substitution of Glutamine for Arginine at codon 958 was detected. The observed variant c.2873G>A (p.Arg958Gln) has not been reported in the 1000 genomes and has a MAF of 0.0002% and 0.001% in the gnomAD databases . The in silico prediction of the variant are possibly damaging by Mutation Taster, DANN, LRT, and SIFT. The reference codon is conserved across species. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.5

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.3

REVEL

Pathogenic

0.69

Sift

Uncertain

0.011

Sift4G

Uncertain

0.023

Polyphen

1.0

Vest4

0.91

MVP

0.93

MPC

0.98

ClinPred

0.93

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.58

gMVP

0.91

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

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