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GeneBe

7-44518625-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000289547.8(NPC1L1):c.3178A>G(p.Thr1060Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)
Exomes 𝑓: 0.0000044 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

NPC1L1
ENST00000289547.8 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.20
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 made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06298214).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NPC1L1NM_001101648.2 linkuse as main transcriptc.3137-1268A>G intron_variant ENST00000381160.8
NPC1L1NM_013389.3 linkuse as main transcriptc.3178A>G p.Thr1060Ala missense_variant 15/20
NPC1L1XM_011515326.4 linkuse as main transcriptc.2942-1268A>G intron_variant
NPC1L1XM_011515328.3 linkuse as main transcriptc.1496-1268A>G intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NPC1L1ENST00000289547.8 linkuse as main transcriptc.3178A>G p.Thr1060Ala missense_variant 15/201 Q9UHC9-1
NPC1L1ENST00000381160.8 linkuse as main transcriptc.3137-1268A>G intron_variant 1 NM_001101648.2 P1
NPC1L1ENST00000546276.5 linkuse as main transcriptc.2999-1268A>G intron_variant 1

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000441
AC:
3
AN:
680044
Hom.:
0
Cov.:
9
AF XY:
0.00000288
AC XY:
1
AN XY:
347384
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000580
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
30
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 07, 2024The c.3178A>G (p.T1060A) alteration is located in exon 15 (coding exon 15) of the NPC1L1 gene. This alteration results from a A to G substitution at nucleotide position 3178, causing the threonine (T) at amino acid position 1060 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.82
Cadd
Benign
2.1
Dann
Benign
0.18
DEOGEN2
Benign
0.059
T
Eigen
Benign
-1.8
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.0010
N
LIST_S2
Benign
0.18
T
M_CAP
Benign
0.0017
T
MetaRNN
Benign
0.063
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.38
N
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.45
T
PROVEAN
Benign
0.070
N
REVEL
Benign
0.024
Sift
Benign
0.25
T
Sift4G
Benign
0.40
T
Vest4
0.085
MutPred
0.43
Gain of helix (P = 0.132);
MVP
0.29
MPC
0.15
ClinPred
0.43
T
GERP RS
-0.61
Varity_R
0.048
gMVP
0.29

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs1316277525; hg19: chr7-44558224; API