rs1140458

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000271.5(NPC1):c.2793C>T(p.Asn931Asn) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.486 in 1,613,394 control chromosomes in the GnomAD database, including 193,282 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.46 ( 16719 hom., cov: 32)

Exomes 𝑓: 0.49 ( 176563 hom. )

Consequence

NPC1
NM_000271.5 splice_region, synonymous

Scores

Splicing: ADA: 0.9915

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15O:1

Conservation

PhyloP100: 4.82

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:

NPC1 (HGNC:):

NPC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 18-23539813-G-A is Benign according to our data. Variant chr18-23539813-G-A is described in ClinVar as [Benign]. Clinvar id is 21136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23539813-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1	NM_000271.5 linkuse as main transcript	c.2793C>T	p.Asn931Asn	splice_region_variant, synonymous_variant	18/25	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.2793C>T	p.Asn931Asn	splice_region_variant, synonymous_variant	18/25	1	NM_000271.5	ENSP00000269228.4		O15118-1

Frequencies

GnomAD3 genomes

AF:

0.462

AC:

70245

AN:

151888

Hom.:

16700

Cov.:

show subpopulations

Gnomad AFR

AF:

0.376

Gnomad AMI

AF:

0.422

Gnomad AMR

AF:

0.572

Gnomad ASJ

AF:

0.308

Gnomad EAS

AF:

0.626

Gnomad SAS

AF:

0.486

Gnomad FIN

AF:

0.520

Gnomad MID

AF:

0.307

Gnomad NFE

AF:

0.477

Gnomad OTH

AF:

0.439

GnomAD3 exomes

AF:

0.499

AC:

125229

AN:

251178

Hom.:

32486

AF XY:

0.492

AC XY:

66862

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.378

Gnomad AMR exome

AF:

0.654

Gnomad ASJ exome

AF:

0.307

Gnomad EAS exome

AF:

0.622

Gnomad SAS exome

AF:

0.487

Gnomad FIN exome

AF:

0.502

Gnomad NFE exome

AF:

0.470

Gnomad OTH exome

AF:

0.467

GnomAD4 exome

AF:

0.488

AC:

713379

AN:

1461388

Hom.:

176563

Cov.:

AF XY:

0.486

AC XY:

353256

AN XY:

727012

show subpopulations

Gnomad4 AFR exome

AF:

0.368

Gnomad4 AMR exome

AF:

0.645

Gnomad4 ASJ exome

AF:

0.303

Gnomad4 EAS exome

AF:

0.656

Gnomad4 SAS exome

AF:

0.491

Gnomad4 FIN exome

AF:

0.497

Gnomad4 NFE exome

AF:

0.485

Gnomad4 OTH exome

AF:

0.468

GnomAD4 genome

AF:

0.463

AC:

70324

AN:

152006

Hom.:

16719

Cov.:

AF XY:

0.467

AC XY:

34675

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.376

Gnomad4 AMR

AF:

0.572

Gnomad4 ASJ

AF:

0.308

Gnomad4 EAS

AF:

0.626

Gnomad4 SAS

AF:

0.487

Gnomad4 FIN

AF:

0.520

Gnomad4 NFE

AF:

0.477

Gnomad4 OTH

AF:

0.444

Alfa

AF:

0.442

Hom.:

9661

Bravo

AF:

0.467

Asia WGS

AF:

0.546

AC:

1899

AN:

3478

EpiCase

AF:

0.455

EpiControl

AF:

0.443

ClinVar

Significance: Benign

Submissions summary: Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Benign:7Other:1

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 19, 2019	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.86

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

SpliceAI score (max)

0.030

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