GeneBe

rs3837910

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000271.5(NPC1):​c.1947+13_1947+16delGGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000533 in 937,566 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 0)
Exomes 𝑓: 0.0000053 ( 0 hom. )

Consequence

NPC1
NM_000271.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.765

Publications

0 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

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
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
NPC1
NM_000271.5
MANE Select
c.1947+13_1947+16delGGGG
intron
N/ANP_000262.2

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
NPC1
ENST00000269228.10
TSL:1 MANE Select
c.1947+13_1947+16delGGGG
intron
N/AENSP00000269228.4
NPC1
ENST00000591051.1
TSL:2
c.1023+13_1023+16delGGGG
intron
N/AENSP00000467636.1
NPC1
ENST00000540608.5
TSL:2
n.1861+13_1861+16delGGGG
intron
N/A

Frequencies

GnomAD3 genomes
Cov.:
0
GnomAD4 exome
AF:
0.00000533
AC:
5
AN:
937566
Hom.:
0
AF XY:
0.00000417
AC XY:
2
AN XY:
479080
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
25944
American (AMR)
AF:
0.00
AC:
0
AN:
36692
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
21158
East Asian (EAS)
AF:
0.00
AC:
0
AN:
27016
South Asian (SAS)
AF:
0.00
AC:
0
AN:
71738
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40376
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4306
European-Non Finnish (NFE)
AF:
0.00000747
AC:
5
AN:
669364
Other (OTH)
AF:
0.00
AC:
0
AN:
40972
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.255
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
PhyloP100
-0.77

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

Other links and lift over

dbSNP: rs3837910; hg19: chr18-21124907; API