GeneBe

7-44541392-T-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001101648.2(NPC1L1):​c.-133A>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000164 in 608,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

NPC1L1
NM_001101648.2 upstream_gene

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.434

Publications

0 publications found
Variant links:
Genes affected
NPC1L1 (HGNC:7898): (NPC1 like intracellular cholesterol transporter 1) The protein encoded by this gene is a multi-pass membrane protein. It contains a conserved N-terminal Niemann-Pick C1 (NPC1) domain and a putative sterol-sensing domain (SSD) which includes a YQRL motif functioning as a plasma membrane to trans-Golgi network transport signal in other proteins. This protein takes up free cholesterol into cells through vesicular endocytosis and plays a critical role in the absorption of intestinal cholesterol. It also has the ability to transport alpha-tocopherol (vitamin E). The drug ezetimibe targets this protein and inhibits the absorption of intestinal cholesterol and alpha-tocopherol. In addition, this protein may play a critical role in regulating lipid metabolism. Polymorphic variations in this gene are associated with plasma total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels and coronary heart disease (CHD) risk. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.76).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPC1L1NM_001101648.2 linkc.-133A>C upstream_gene_variant ENST00000381160.8 NP_001095118.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NPC1L1ENST00000381160.8 linkc.-133A>C upstream_gene_variant 1 NM_001101648.2 ENSP00000370552.3
NPC1L1ENST00000289547.8 linkc.-133A>C upstream_gene_variant 1 ENSP00000289547.4
NPC1L1ENST00000546276.5 linkc.-133A>C upstream_gene_variant 1 ENSP00000438033.1
NPC1L1ENST00000423141.1 linkc.-133A>C upstream_gene_variant 1 ENSP00000404670.1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000164
AC:
1
AN:
608478
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
312504
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
16154
American (AMR)
AF:
0.00
AC:
0
AN:
21844
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
14922
East Asian (EAS)
AF:
0.00
AC:
0
AN:
31584
South Asian (SAS)
AF:
0.00
AC:
0
AN:
49500
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
31540
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
3898
European-Non Finnish (NFE)
AF:
0.00000245
AC:
1
AN:
407534
Other (OTH)
AF:
0.00
AC:
0
AN:
31502
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.76
CADD
Benign
13
DANN
Benign
0.76
PhyloP100
-0.43
PromoterAI
0.20
Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs17655652; hg19: chr7-44580991; API