rs217428
Positions:
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1
The NM_001101648.2(NPC1L1):c.3634-9A>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,611,844 control chromosomes in the GnomAD database, including 52,495 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).
Frequency
Genomes: 𝑓 0.25 ( 5120 hom., cov: 31)
Exomes 𝑓: 0.25 ( 47375 hom. )
Consequence
NPC1L1
NM_001101648.2 splice_polypyrimidine_tract, intron
NM_001101648.2 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.00001679
2
Clinical Significance
Conservation
PhyloP100: -1.04
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 made for transcript
Verdict is Benign. Variant got -14 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.93).
BP6
?
Variant 7-44515974-T-G is Benign according to our data. Variant chr7-44515974-T-G is described in ClinVar as [Benign]. Clinvar id is 403257.Status of the report is criteria_provided_single_submitter, 1 stars.
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC1L1 | NM_001101648.2 | c.3634-9A>C | splice_polypyrimidine_tract_variant, intron_variant | ENST00000381160.8 | |||
NPC1L1 | NM_013389.3 | c.3715-9A>C | splice_polypyrimidine_tract_variant, intron_variant | ||||
NPC1L1 | XM_011515326.4 | c.3439-9A>C | splice_polypyrimidine_tract_variant, intron_variant | ||||
NPC1L1 | XM_011515328.3 | c.1993-9A>C | splice_polypyrimidine_tract_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1L1 | ENST00000381160.8 | c.3634-9A>C | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_001101648.2 | P1 | |||
NPC1L1 | ENST00000289547.8 | c.3715-9A>C | splice_polypyrimidine_tract_variant, intron_variant | 1 | |||||
NPC1L1 | ENST00000546276.5 | c.3496-9A>C | splice_polypyrimidine_tract_variant, intron_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.250 AC: 37798AN: 151122Hom.: 5105 Cov.: 31
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GnomAD3 exomes AF: 0.211 AC: 52338AN: 247858Hom.: 6576 AF XY: 0.212 AC XY: 28429AN XY: 134160
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GnomAD4 exome AF: 0.248 AC: 361547AN: 1460606Hom.: 47375 Cov.: 38 AF XY: 0.245 AC XY: 177826AN XY: 726524
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GnomAD4 genome ? AF: 0.250 AC: 37850AN: 151238Hom.: 5120 Cov.: 31 AF XY: 0.247 AC XY: 18209AN XY: 73856
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ClinVar
Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 29, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at