rs12970899

Positions:

• chr18-23568899-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000271.5(NPC1):​c.387T>C​(p.Tyr129=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,613,482 control chromosomes in the GnomAD database, including 20,628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1617 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19011 hom.)
• Consequence: NPC1 NM_000271.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.0660

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 18-23568899-A-G is Benign according to our data. Variant chr18-23568899-A-G is described in ClinVar as [Benign]. Clinvar id is 129811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23568899-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.066 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1	NM_000271.5	c.387T>C	p.Tyr129=	synonymous_variant	4/25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.387T>C	p.Tyr129=	synonymous_variant	4/25	1	NM_000271.5	ENSP00000269228	P1
NPC1	ENST00000540608.5	n.301T>C		non_coding_transcript_exon_variant	2/16	2

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20273 AN: 152138 Hom.: 1619 Cov.: 32

Gnomad AFR AF: 0.0677

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.0177

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.166

GnomAD3 exomes AF: 0.144 AC: 36100 AN: 251370 Hom.: 3192 AF XY: 0.152 AC XY: 20638 AN XY: 135856

Gnomad AFR exome AF: 0.0666

Gnomad AMR exome AF: 0.0926

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.0157

Gnomad SAS exome AF: 0.187

Gnomad FIN exome AF: 0.138

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.156 AC: 227543 AN: 1461226 Hom.: 19011 Cov.: 32 AF XY: 0.158 AC XY: 114914 AN XY: 726988

Gnomad4 AFR exome AF: 0.0664

Gnomad4 AMR exome AF: 0.0984

Gnomad4 ASJ exome AF: 0.272

Gnomad4 EAS exome AF: 0.0128

Gnomad4 SAS exome AF: 0.183

Gnomad4 FIN exome AF: 0.144

Gnomad4 NFE exome AF: 0.161

Gnomad4 OTH exome AF: 0.162

GnomAD4 genome AF: 0.133 AC: 20266 AN: 152256 Hom.: 1617 Cov.: 32 AF XY: 0.134 AC XY: 10003 AN XY: 74442

Gnomad4 AFR AF: 0.0678

Gnomad4 AMR AF: 0.131

Gnomad4 ASJ AF: 0.277

Gnomad4 EAS AF: 0.0177

Gnomad4 SAS AF: 0.190

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.168

Gnomad4 OTH AF: 0.164

Alfa AF: 0.167 Hom.: 3825

Bravo AF: 0.128

Asia WGS AF: 0.105 AC: 367 AN: 3478

EpiCase AF: 0.182

EpiControl AF: 0.180

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Niemann-Pick disease, type C1 Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 06, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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	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, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.1
DANN	Benign	0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs12970899; hg19: chr18-21148863;