rs3745024

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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

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 -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/exons	MANE	Protein	UniProt
NPC1	NM_000271.5	c.1947+14G>T		intron_variant		ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.1947+14G>T		intron_variant		1	NM_000271.5	ENSP00000269228	P1
NPC1	ENST00000591051.1	c.1025+14G>T		intron_variant		2		ENSP00000467636
NPC1	ENST00000540608.5	n.1861+14G>T		intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes AF: 0.0449 AC: 10474 AN: 233216 Hom.: 1029 AF XY: 0.0436 AC XY: 5533 AN XY: 126904

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

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.: 27 AF XY: 0.0236 AC XY: 1572 AN XY: 66574

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.: 32

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 14, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 02, 2020	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. -

Niemann-Pick disease, type C1 Benign:5

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	May 10, 2016	- -
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	Genome-Nilou Lab	Jun 10, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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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

Other links and lift over

dbSNP: rs3745024; hg19: chr18-21124910;