Variant rs6507720 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000271.5(NPC1):c.2911+28T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.505 in 1,523,196 control chromosomes in the GnomAD database, including 198,353 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.56 ( 24469 hom., cov: 33)

Exomes 𝑓: 0.50 ( 173884 hom. )

Consequence

NPC1
NM_000271.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.445

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 18-23539327-A-G is Benign according to our data. Variant chr18-23539327-A-G is described in ClinVar as [Benign]. Clinvar id is 255695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23539327-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5 linkuse as main transcript	c.2911+28T>C		intron_variant		ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10 linkuse as main transcript	c.2911+28T>C	intron_variant	1	NM_000271.5	P1	O15118-1
NPC1	ENST00000591051.1 linkuse as main transcript	c.1989+28T>C	intron_variant	2
NPC1	ENST00000591075.1 linkuse as main transcript	n.544+28T>C	intron_variant, non_coding_transcript_variant	4

Frequencies

GnomAD3 genomes

AF:

0.556

AC:

84552

AN:

152008

Hom.:

24425

Cov.:

show subpopulations

Gnomad AFR

AF:

0.703

Gnomad AMI

AF:

0.424

Gnomad AMR

AF:

0.603

Gnomad ASJ

AF:

0.308

Gnomad EAS

AF:

0.626

Gnomad SAS

AF:

0.499

Gnomad FIN

AF:

0.519

Gnomad MID

AF:

0.329

Gnomad NFE

AF:

0.479

Gnomad OTH

AF:

0.493

GnomAD3 exomes

AF:

0.525

AC:

129031

AN:

245706

Hom.:

35166

AF XY:

0.512

AC XY:

67950

AN XY:

132600

show subpopulations

Gnomad AFR exome

AF:

0.713

Gnomad AMR exome

AF:

0.671

Gnomad ASJ exome

AF:

0.307

Gnomad EAS exome

AF:

0.623

Gnomad SAS exome

AF:

0.498

Gnomad FIN exome

AF:

0.503

Gnomad NFE exome

AF:

0.471

Gnomad OTH exome

AF:

0.477

GnomAD4 exome

AF:

0.499

AC:

684094

AN:

1371070

Hom.:

173884

Cov.:

AF XY:

0.495

AC XY:

340004

AN XY:

686280

show subpopulations

Gnomad4 AFR exome

AF:

0.703

Gnomad4 AMR exome

AF:

0.663

Gnomad4 ASJ exome

AF:

0.303

Gnomad4 EAS exome

AF:

0.657

Gnomad4 SAS exome

AF:

0.502

Gnomad4 FIN exome

AF:

0.497

Gnomad4 NFE exome

AF:

0.486

Gnomad4 OTH exome

AF:

0.489

GnomAD4 genome

AF:

0.557

AC:

84661

AN:

152126

Hom.:

24469

Cov.:

AF XY:

0.557

AC XY:

41421

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.703

Gnomad4 AMR

AF:

0.603

Gnomad4 ASJ

AF:

0.308

Gnomad4 EAS

AF:

0.626

Gnomad4 SAS

AF:

0.500

Gnomad4 FIN

AF:

0.519

Gnomad4 NFE

AF:

0.479

Gnomad4 OTH

AF:

0.500

Alfa

AF:

0.468

Hom.:

17738

Bravo

AF:

0.572

Asia WGS

AF:

0.571

AC:

1984

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 20, 2015	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Niemann-Pick disease, type C1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.1

DANN

Benign

0.39

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