rs151084683

Positions:

• chr18-23561379-G-A
• chr18-23561379-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000271.5(NPC1):​c.612C>T​(p.Thr204=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,614,192 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (65 hom.)
• Consequence: NPC1 NM_000271.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.10

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 18-23561379-G-A is Benign according to our data. Variant chr18-23561379-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 197651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23561379-G-A is described in Lovd as [Likely_benign]. Variant chr18-23561379-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00223 (340/152314) while in subpopulation SAS AF= 0.0319 (154/4826). AF 95% confidence interval is 0.0278. There are 4 homozygotes in gnomad4. There are 206 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5	c.612C>T	p.Thr204=	synonymous_variant	5/25	ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.612C>T	p.Thr204=	synonymous_variant	5/25	1	NM_000271.5	P1
NPC1	ENST00000540608.5	n.526C>T		non_coding_transcript_exon_variant	3/16	2

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 340 AN: 152196 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00769

Gnomad SAS AF: 0.0319

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00496 AC: 1247 AN: 251472 Hom.: 21 AF XY: 0.00633 AC XY: 860 AN XY: 135908

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00549

Gnomad SAS exome AF: 0.0295

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00308 AC: 4502 AN: 1461878 Hom.: 65 Cov.: 32 AF XY: 0.00384 AC XY: 2791 AN XY: 727240

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00330

Gnomad4 SAS exome AF: 0.0275

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.00430

GnomAD4 genome AF: 0.00223 AC: 340 AN: 152314 Hom.: 4 Cov.: 32 AF XY: 0.00277 AC XY: 206 AN XY: 74474

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00713

Gnomad4 SAS AF: 0.0319

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00147

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.00142

Asia WGS AF: 0.0230 AC: 81 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2019	- -

Niemann-Pick disease, type C1 Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 02, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.6
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs151084683; hg19: chr18-21141343; COSMIC: COSV52577334; COSMIC: COSV52577334;