Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 5P and 13B. PM1PM5PP2BP4_StrongBP6BS1BS2

The NM_000271.5(NPC1):c.2882A>G(p.Asn961Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000607 in 1,613,762 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0032 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00033 ( 2 hom. )

Consequence

NPC1
NM_000271.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 4.14

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

Niemann-Pick disease, type C1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Myriad Women’s Health
Niemann-Pick disease type C, adult neurologic onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Niemann-Pick disease type C, juvenile neurologic onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Niemann-Pick disease type C, late infantile neurologic onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Niemann-Pick disease type C, severe early infantile neurologic onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Niemann-Pick disease type C, severe perinatal form
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NPC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000271.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr18-23539369-AACTGGTCAGTGATAT-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1705777.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 171 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: 1.0917 (below the threshold of 3.09). Trascript score misZ: 1.706 (below the threshold of 3.09). GenCC associations: The gene is linked to Niemann-Pick disease, type C1, Niemann-Pick disease type C, severe early infantile neurologic onset, Niemann-Pick disease type C, late infantile neurologic onset, Niemann-Pick disease type C, adult neurologic onset, Niemann-Pick disease type C, juvenile neurologic onset, Niemann-Pick disease type C, severe perinatal form.

BP4

Computational evidence support a benign effect (MetaRNN=0.007890493).

BP6

Variant 18-23539384-T-C is Benign according to our data. Variant chr18-23539384-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 252475.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00325 (495/152360) while in subpopulation AFR AF = 0.0113 (471/41572). AF 95% confidence interval is 0.0105. There are 4 homozygotes in GnomAd4. There are 243 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000271.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1	NM_000271.5	MANE Select	c.2882A>G	p.Asn961Ser	missense	Exon 19 of 25	NP_000262.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPC1	ENST00000269228.10	TSL:1 MANE Select	c.2882A>G	p.Asn961Ser	missense	Exon 19 of 25	ENSP00000269228.4
NPC1	ENST00000591051.1	TSL:2	c.1958A>G	p.Asn653Ser	missense	Exon 12 of 18	ENSP00000467636.1
NPC1	ENST00000591075.1	TSL:4	n.515A>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.00323

AC:

492

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.000848

AC:

213

AN:

251206

AF XY:

0.000685

show subpopulations

Gnomad AFR exome

AF:

0.0118

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000332

AC:

485

AN:

1461402

Hom.:

Cov.:

AF XY:

0.000304

AC XY:

221

AN XY:

727004

show subpopulations

African (AFR)

AF:

0.0114

AC:

380

AN:

33470

American (AMR)

AF:

0.000335

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000270

AC:

AN:

1111642

Other (OTH)

AF:

0.000845

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00325

AC:

495

AN:

152360

Hom.:

Cov.:

AF XY:

0.00326

AC XY:

243

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.0113

AC:

471

AN:

41572

American (AMR)

AF:

0.000719

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68042

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00133

Hom.:

Bravo

AF:

0.00345

ESP6500AA

AF:

0.0127

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00108

AC:

131

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Niemann-Pick disease, type C1 (3)

not specified (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.37

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.59

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0079

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

1.7

PhyloP100

4.1

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.41

Sift

Benign

0.36

Sift4G

Benign

0.44

Polyphen

0.034

Vest4

0.74

MVP

0.75

MPC

0.28

ClinPred

0.022

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.45

gMVP

0.77

Mutation Taster

=59/41

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs34084984

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over