rs1140458

chr18-23539813-G-Achr18-23539813-G-Cchr18-23539813-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000271.5(NPC1):c.2793C>T(p.Asn931=) 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:14 O:1
• Conservation: PhyloP100: 4.82

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 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	UniProt
NPC1	NM_000271.5	c.2793C>T	p.Asn931=	splice_region_variant, synonymous_variant	18/25	ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.2793C>T	p.Asn931=	splice_region_variant, synonymous_variant	18/25	1	NM_000271.5	P1

Frequencies

GnomAD3 genomes AF: 0.462 AC: 70245 AN: 151888 Hom.: 16700 Cov.: 32

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

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.: 43 AF XY: 0.486 AC XY: 353256 AN XY: 727012

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.: 32 AF XY: 0.467 AC XY: 34675 AN XY: 74272

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:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type C1 Benign:7 Other:1

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, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 22, 2016	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
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	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 19, 2019	- -

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 21, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
Cadd	Benign	16
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

Other links and lift over

dbSNP: rs1140458; hg19: chr18-21119777; COSMIC: COSV52579121; COSMIC: COSV52579121;