rs3745024

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000271.5(NPC1):c.1947+14G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 1,329,592 control chromosomes in the GnomAD database, including 3,271 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 381 hom., cov: 27)

Exomes 𝑓: 0.022 ( 2890 hom. )

Consequence

NPC1
NM_000271.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.765

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 18-23544946-C-A is Benign according to our data. Variant chr18-23544946-C-A is described in ClinVar as [Benign]. Clinvar id is 92704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23544946-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5 link	c.1947+14G>T		intron_variant	Intron 12 of 24	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPC1	ENST00000269228.10 link	c.1947+14G>T	intron_variant	Intron 12 of 24	1	NM_000271.5	ENSP00000269228.4	O15118-1
NPC1	ENST00000591051.1 link	c.1023+14G>T	intron_variant	Intron 5 of 17	2		ENSP00000467636.1	K7EQ23
NPC1	ENST00000540608.5 link	n.1861+14G>T	intron_variant	Intron 10 of 15	2

Frequencies

GnomAD3 genomes

AF:

0.0216

AC:

2931

AN:

135898

Hom.:

383

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00511

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0180

Gnomad ASJ

AF:

0.00726

Gnomad EAS

AF:

0.317

Gnomad SAS

AF:

0.0878

Gnomad FIN

AF:

0.0137

Gnomad MID

AF:

0.0233

Gnomad NFE

AF:

0.00878

Gnomad OTH

AF:

0.0214

GnomAD3 exomes

AF:

0.0449

AC:

10474

AN:

233216

Hom.:

1029

AF XY:

0.0436

AC XY:

5533

AN XY:

126904

show subpopulations

Gnomad AFR exome

AF:

0.00465

Gnomad AMR exome

AF:

0.0491

Gnomad ASJ exome

AF:

0.00771

Gnomad EAS exome

AF:

0.305

Gnomad SAS exome

AF:

0.0722

Gnomad FIN exome

AF:

0.0151

Gnomad NFE exome

AF:

0.00826

Gnomad OTH exome

AF:

0.0286

GnomAD4 exome

AF:

0.0218

AC:

25990

AN:

1193600

Hom.:

2890

Cov.:

AF XY:

0.0233

AC XY:

14066

AN XY:

602878

show subpopulations

Gnomad4 AFR exome

AF:

0.00314

Gnomad4 AMR exome

AF:

0.0439

Gnomad4 ASJ exome

AF:

0.00797

Gnomad4 EAS exome

AF:

0.328

Gnomad4 SAS exome

AF:

0.0706

Gnomad4 FIN exome

AF:

0.0153

Gnomad4 NFE exome

AF:

0.00598

Gnomad4 OTH exome

AF:

0.0321

GnomAD4 genome

AF:

0.0215

AC:

2924

AN:

135992

Hom.:

381

Cov.:

AF XY:

0.0236

AC XY:

1572

AN XY:

66574

show subpopulations

Gnomad4 AFR

AF:

0.00509

Gnomad4 AMR

AF:

0.0180

Gnomad4 ASJ

AF:

0.00726

Gnomad4 EAS

AF:

0.317

Gnomad4 SAS

AF:

0.0879

Gnomad4 FIN

AF:

0.0137

Gnomad4 NFE

AF:

0.00879

Gnomad4 OTH

AF:

0.0206

Alfa

AF:

0.0105

Hom.:

Bravo

AF:

0.0201

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Mar 14, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 02, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NPC1 c.1947+14G>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.045 in 233216 control chromosomes in the gnomAD database, including 1029 homozygotes. The observed variant frequency is approximately 16-fold the estimated maximal expected allele frequency for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C phenotype (0.0028), strongly suggesting that the variant is benign. c.1947+14G>T has been reported in the literature in individuals affected with Niemann-Pick Disease Type C (e.g. DeCastro-Oros_2017). These reports do not provide unequivocal conclusions about association of the variant with Niemann-Pick Disease Type C. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Niemann-Pick disease, type C1

Benign:5

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 10, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.1

DANN

Benign

0.39

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