rs10264715
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Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1
The NM_001101648.2(NPC1L1):c.3792C>T(p.Tyr1264=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,613,972 control chromosomes in the GnomAD database, including 36,381 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).
Frequency
Genomes: 𝑓 0.16 ( 2531 hom., cov: 32)
Exomes 𝑓: 0.21 ( 33850 hom. )
Consequence
NPC1L1
NM_001101648.2 synonymous
NM_001101648.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.25
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 -15 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.55).
BP6
?
Variant 7-44515807-G-A is Benign according to our data. Variant chr7-44515807-G-A is described in ClinVar as [Benign]. Clinvar id is 403256.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
Synonymous conserved (PhyloP=1.25 with no splicing effect.
BA1
?
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC1L1 | NM_001101648.2 | c.3792C>T | p.Tyr1264= | synonymous_variant | 18/19 | ENST00000381160.8 | |
NPC1L1 | NM_013389.3 | c.3873C>T | p.Tyr1291= | synonymous_variant | 19/20 | ||
NPC1L1 | XM_011515326.4 | c.3597C>T | p.Tyr1199= | synonymous_variant | 17/18 | ||
NPC1L1 | XM_011515328.3 | c.2151C>T | p.Tyr717= | synonymous_variant | 15/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1L1 | ENST00000381160.8 | c.3792C>T | p.Tyr1264= | synonymous_variant | 18/19 | 1 | NM_001101648.2 | P1 | |
NPC1L1 | ENST00000289547.8 | c.3873C>T | p.Tyr1291= | synonymous_variant | 19/20 | 1 | |||
NPC1L1 | ENST00000546276.5 | c.3654C>T | p.Tyr1218= | synonymous_variant | 17/18 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.158 AC: 24021AN: 152054Hom.: 2532 Cov.: 32
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GnomAD3 exomes AF: 0.166 AC: 41709AN: 251038Hom.: 4542 AF XY: 0.169 AC XY: 22932AN XY: 135690
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GnomAD4 exome AF: 0.206 AC: 301785AN: 1461800Hom.: 33850 Cov.: 36 AF XY: 0.204 AC XY: 148396AN XY: 727194
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GnomAD4 genome ? AF: 0.158 AC: 24016AN: 152172Hom.: 2531 Cov.: 32 AF XY: 0.156 AC XY: 11606AN XY: 74374
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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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BayesDel_noAF
Benign
CADD
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DANN
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RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at