rs145362908

chr18-23541154-C-Achr18-23541154-C-Gchr18-23541154-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000271.5(NPC1):c.2428G>T(p.Val810Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000437 in 1,614,192 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V810I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (2 hom.)
• Consequence: NPC1 NM_000271.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: -1.83

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067704916).
• BP6: Variant 18-23541154-C-A is Benign according to our data. Variant chr18-23541154-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 499327.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000439 (642/1461878) while in subpopulation AMR AF= 0.0023 (103/44724). AF 95% confidence interval is 0.00194. There are 2 homozygotes in gnomad4_exome. There are 318 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5	c.2428G>T	p.Val810Phe	missense_variant	16/25	ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.2428G>T	p.Val810Phe	missense_variant	16/25	1	NM_000271.5	P1
NPC1	ENST00000591051.1	c.1507G>T	p.Val503Phe	missense_variant	9/18	2
NPC1	ENST00000540608.5	n.2342G>T		non_coding_transcript_exon_variant	14/16	2
NPC1	ENST00000586718.1	n.219G>T		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000541 AC: 136 AN: 251482 Hom.: 0 AF XY: 0.000515 AC XY: 70 AN XY: 135912

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000439 AC: 642 AN: 1461878 Hom.: 2 Cov.: 32 AF XY: 0.000437 AC XY: 318 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00230

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000458

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74480

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000293 Hom.: 0

Bravo AF: 0.000703

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000453 AC: 55

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Niemann-Pick disease, type C1 Uncertain:3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 11, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 29, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2020	- -

NPC1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 10, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	0.23
Dann	Benign	0.96
DEOGEN2	Benign	0.36	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.23
Sift	Benign	0.085	T
Sift4G	Benign	0.084	T
Polyphen		0.026	B
Vest4		0.31
MVP		0.55
MPC		0.34
ClinPred		0.031	T
GERP RS		-9.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.41

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: rs145362908; hg19: chr18-21121118;