rs2510344

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000271.5(NPC1):c.3754+34A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 1,594,024 control chromosomes in the GnomAD database, including 195,399 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 18597 hom., cov: 33)

Exomes 𝑓: 0.49 ( 176802 hom. )

Consequence

NPC1
NM_000271.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.654

Publications

27 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 18-23533321-T-C is Benign according to our data. Variant chr18-23533321-T-C is described in ClinVar as Benign. ClinVar VariationId is 255700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5 link	c.3754+34A>G		intron_variant	Intron 24 of 24	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10 link	c.3754+34A>G		intron_variant	Intron 24 of 24	1	NM_000271.5	ENSP00000269228.4		O15118-1

Frequencies

GnomAD3 genomes

AF:

0.492

AC:

74718

AN:

151976

Hom.:

18576

Cov.:

show subpopulations

Gnomad AFR

AF:

0.475

Gnomad AMI

AF:

0.424

Gnomad AMR

AF:

0.582

Gnomad ASJ

AF:

0.307

Gnomad EAS

AF:

0.624

Gnomad SAS

AF:

0.498

Gnomad FIN

AF:

0.520

Gnomad MID

AF:

0.329

Gnomad NFE

AF:

0.479

Gnomad OTH

AF:

0.461

GnomAD2 exomes

AF:

0.508

AC:

127350

AN:

250732

AF XY:

0.500

show subpopulations

Gnomad AFR exome

AF:

0.480

Gnomad AMR exome

AF:

0.659

Gnomad ASJ exome

AF:

0.306

Gnomad EAS exome

AF:

0.621

Gnomad FIN exome

AF:

0.503

Gnomad NFE exome

AF:

0.471

Gnomad OTH exome

AF:

0.470

GnomAD4 exome

AF:

0.492

AC:

708936

AN:

1441930

Hom.:

176802

Cov.:

AF XY:

0.489

AC XY:

351693

AN XY:

718592

show subpopulations

African (AFR)

AF:

0.471

AC:

15593

AN:

33078

American (AMR)

AF:

0.650

AC:

29074

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.303

AC:

7867

AN:

25992

East Asian (EAS)

AF:

0.657

AC:

26001

AN:

39600

South Asian (SAS)

AF:

0.502

AC:

43104

AN:

85830

European-Finnish (FIN)

AF:

0.498

AC:

26574

AN:

53370

Middle Eastern (MID)

AF:

0.355

AC:

2030

AN:

5724

European-Non Finnish (NFE)

AF:

0.485

AC:

530327

AN:

1093910

Other (OTH)

AF:

0.475

AC:

28366

AN:

59728

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

18349

36698

55048

73397

91746

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15692

31384

47076

62768

78460

<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:

0.492

AC:

74800

AN:

152094

Hom.:

18597

Cov.:

AF XY:

0.495

AC XY:

36825

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.475

AC:

19702

AN:

41486

American (AMR)

AF:

0.582

AC:

8898

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.307

AC:

1066

AN:

3468

East Asian (EAS)

AF:

0.624

AC:

3228

AN:

5172

South Asian (SAS)

AF:

0.499

AC:

2404

AN:

4818

European-Finnish (FIN)

AF:

0.520

AC:

5490

AN:

10566

Middle Eastern (MID)

AF:

0.330

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.479

AC:

32546

AN:

67982

Other (OTH)

AF:

0.465

AC:

982

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1962

3925

5887

7850

9812

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

674

1348

2022

2696

3370

<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:

0.477

Hom.:

48199

Bravo

AF:

0.499

Asia WGS

AF:

0.564

AC:

1961

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Niemann-Pick disease, type C1

Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.6

(source)

DANN

Benign

0.46

PhyloP100

-0.65

PromoterAI

0.0096

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over