rs80358251

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM5BP4_StrongBP6BS1BS2

The NM_000271.5(NPC1):c.709C>T(p.Pro237Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,614,168 control chromosomes in the GnomAD database, including 195 homozygotes. In-silico tool predicts 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. P237L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.010 ( 17 hom., cov: 32)

Exomes 𝑓: 0.014 ( 178 hom. )

Consequence

NPC1
NM_000271.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:14O:1

Conservation

PhyloP100: 8.19

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr18-23560402-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.013225466).

BP6

Variant 18-23560403-G-A is Benign according to our data. Variant chr18-23560403-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 21142.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=6, Uncertain_significance=1, not_provided=1}. Variant chr18-23560403-G-A is described in Lovd as [Benign]. Variant chr18-23560403-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.01 (1528/152344) while in subpopulation NFE AF= 0.0162 (1100/68034). AF 95% confidence interval is 0.0154. There are 17 homozygotes in gnomad4. There are 720 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5 link	c.709C>T	p.Pro237Ser	missense_variant	Exon 6 of 25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPC1	ENST00000269228.10 link	c.709C>T	p.Pro237Ser	missense_variant	Exon 6 of 25	1	NM_000271.5	ENSP00000269228.4	O15118-1
NPC1	ENST00000540608.5 link	n.623C>T		non_coding_transcript_exon_variant	Exon 4 of 16	2
NPC1	ENST00000591051.1 link	c.-63C>T		upstream_gene_variant		2		ENSP00000467636.1	K7EQ23

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

1530

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00277

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00543

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.0186

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0162

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00988

AC:

2478

AN:

250694

Hom.:

AF XY:

0.00961

AC XY:

1302

AN XY:

135546

show subpopulations

Gnomad AFR exome

AF:

0.00296

Gnomad AMR exome

AF:

0.00370

Gnomad ASJ exome

AF:

0.00289

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000850

Gnomad FIN exome

AF:

0.0177

Gnomad NFE exome

AF:

0.0159

Gnomad OTH exome

AF:

0.0105

GnomAD4 exome

AF:

0.0138

AC:

20169

AN:

1461824

Hom.:

178

Cov.:

AF XY:

0.0133

AC XY:

9695

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00212

Gnomad4 AMR exome

AF:

0.00423

Gnomad4 ASJ exome

AF:

0.00314

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00103

Gnomad4 FIN exome

AF:

0.0198

Gnomad4 NFE exome

AF:

0.0161

Gnomad4 OTH exome

AF:

0.0120

GnomAD4 genome

AF:

0.0100

AC:

1528

AN:

152344

Hom.:

Cov.:

AF XY:

0.00966

AC XY:

720

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00277

Gnomad4 AMR

AF:

0.00542

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.0186

Gnomad4 NFE

AF:

0.0162

Gnomad4 OTH

AF:

0.00614

Alfa

AF:

0.0140

Hom.:

Bravo

AF:

0.00840

TwinsUK

AF:

0.0202

AC:

ALSPAC

AF:

0.0150

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0159

AC:

137

ExAC

AF:

0.0104

AC:

1263

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0144

EpiControl

AF:

0.0133

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:14Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1

Uncertain:1Benign:5Other:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 22, 2014

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Sep 07, 2017

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Benign, for Niemann-Pick disease, type C1, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:12554680). BS1 => Allele frequency is greater than expected for disorder (PMID:11182931). BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 18, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:5

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 24, 2015

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

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Feb 21, 2018

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 32222928, 29631617, 28328115, 25842391, 10480349, 20981092, 12955717, 12554680, 22995991, 25497598, 20489167) -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nasopharyngeal carcinoma

Benign:1

Sep 11, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Uncertain

0.11

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Uncertain

0.43

Eigen

Benign

-0.12

Eigen_PC

Benign

0.012

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.013

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.2

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.40

Sift

Benign

0.41

Sift4G

Benign

0.52

Polyphen

0.0030

Vest4

0.42

MPC

0.27

ClinPred

0.076

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.73

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over