rs3745024

Variant names:

• chr18-23544946-C-A
• rs3745024
• NM_000271.5:c.1947+14G>T

Your query was ambiguous. Multiple possible variants found:

• chr18-23544946-C-A
• chr18-23544946-C-G
• chr18-23544946-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.765
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• Niemann-Pick disease, type C1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Myriad Women’s Health
• Niemann-Pick disease type C, adult neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, juvenile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, late infantile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, severe early infantile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, severe perinatal form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar as Benign. Clinvar id is 92704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	c.1947+14G>T		intron_variant	Intron 12 of 24	ENST00000269228.10	NP_000262.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 2931 AN: 135898 Hom.: 383 Cov.: 27

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

GnomAD2 exomes AF: 0.0449 AC: 10474 AN: 233216 AF XY: 0.0436

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 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.: 24 AF XY: 0.0233 AC XY: 14066 AN XY: 602878

African (AFR) AF: 0.00314 AC: 95 AN: 30276

American (AMR) AF: 0.0439 AC: 1828 AN: 41608

Ashkenazi Jewish (ASJ) AF: 0.00797 AC: 196 AN: 24580

East Asian (EAS) AF: 0.328 AC: 10548 AN: 32156

South Asian (SAS) AF: 0.0706 AC: 5594 AN: 79200

European-Finnish (FIN) AF: 0.0153 AC: 726 AN: 47572

Middle Eastern (MID) AF: 0.0198 AC: 104 AN: 5262

European-Non Finnish (NFE) AF: 0.00598 AC: 5275 AN: 882278

Other (OTH) AF: 0.0321 AC: 1624 AN: 50668

GnomAD4 genome AF: 0.0215 AC: 2924 AN: 135992 Hom.: 381 Cov.: 27 AF XY: 0.0236 AC XY: 1572 AN XY: 66574

African (AFR) AF: 0.00509 AC: 187 AN: 36722

American (AMR) AF: 0.0180 AC: 249 AN: 13826

Ashkenazi Jewish (ASJ) AF: 0.00726 AC: 24 AN: 3304

East Asian (EAS) AF: 0.317 AC: 1391 AN: 4392

South Asian (SAS) AF: 0.0879 AC: 359 AN: 4086

European-Finnish (FIN) AF: 0.0137 AC: 134 AN: 9770

Middle Eastern (MID) AF: 0.0214 AC: 6 AN: 280

European-Non Finnish (NFE) AF: 0.00879 AC: 535 AN: 60898

Other (OTH) AF: 0.0206 AC: 39 AN: 1892

Alfa AF: 0.0119 Hom.: 51

Bravo AF: 0.0201

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

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

- -

-

PreventionGenetics, part of Exact Sciences

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. -

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Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Niemann-Pick disease, type C1 Benign:5

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. -

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

not provided Benign:1

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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
PhyloP100		-0.77
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3745024; hg19: chr18-21124910;