Menu
GeneBe

rs217434

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_001101648.2(NPC1L1):c.3807T>C(p.Val1269=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,612,656 control chromosomes in the GnomAD database, including 29,821 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.17 ( 2426 hom., cov: 32)
Exomes 𝑓: 0.19 ( 27395 hom. )

Consequence

NPC1L1
NM_001101648.2 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.508
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 7-44513639-A-G is Benign according to our data. Variant chr7-44513639-A-G is described in ClinVar as [Benign]. Clinvar id is 403255.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
Synonymous conserved (PhyloP=0.508 with no splicing effect.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NPC1L1NM_001101648.2 linkuse as main transcriptc.3807T>C p.Val1269= synonymous_variant 19/19 ENST00000381160.8
NPC1L1NM_013389.3 linkuse as main transcriptc.3888T>C p.Val1296= synonymous_variant 20/20
NPC1L1XM_011515326.4 linkuse as main transcriptc.3612T>C p.Val1204= synonymous_variant 18/18
NPC1L1XM_011515328.3 linkuse as main transcriptc.2166T>C p.Val722= synonymous_variant 16/16

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NPC1L1ENST00000381160.8 linkuse as main transcriptc.3807T>C p.Val1269= synonymous_variant 19/191 NM_001101648.2 P1
NPC1L1ENST00000289547.8 linkuse as main transcriptc.3888T>C p.Val1296= synonymous_variant 20/201 Q9UHC9-1
NPC1L1ENST00000546276.5 linkuse as main transcriptc.3669T>C p.Val1223= synonymous_variant 18/181

Frequencies

GnomAD3 genomes
AF:
0.172
AC:
26083
AN:
152040
Hom.:
2419
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.156
Gnomad AMI
AF:
0.135
Gnomad AMR
AF:
0.113
Gnomad ASJ
AF:
0.189
Gnomad EAS
AF:
0.00558
Gnomad SAS
AF:
0.140
Gnomad FIN
AF:
0.195
Gnomad MID
AF:
0.114
Gnomad NFE
AF:
0.206
Gnomad OTH
AF:
0.148
GnomAD3 exomes
AF:
0.159
AC:
39467
AN:
248704
Hom.:
3754
AF XY:
0.163
AC XY:
21883
AN XY:
134658
show subpopulations
Gnomad AFR exome
AF:
0.156
Gnomad AMR exome
AF:
0.0778
Gnomad ASJ exome
AF:
0.190
Gnomad EAS exome
AF:
0.00239
Gnomad SAS exome
AF:
0.156
Gnomad FIN exome
AF:
0.195
Gnomad NFE exome
AF:
0.201
Gnomad OTH exome
AF:
0.165
GnomAD4 exome
AF:
0.189
AC:
275342
AN:
1460498
Hom.:
27395
Cov.:
33
AF XY:
0.188
AC XY:
136616
AN XY:
726590
show subpopulations
Gnomad4 AFR exome
AF:
0.162
Gnomad4 AMR exome
AF:
0.0825
Gnomad4 ASJ exome
AF:
0.192
Gnomad4 EAS exome
AF:
0.00416
Gnomad4 SAS exome
AF:
0.162
Gnomad4 FIN exome
AF:
0.194
Gnomad4 NFE exome
AF:
0.202
Gnomad4 OTH exome
AF:
0.182
GnomAD4 genome
AF:
0.172
AC:
26110
AN:
152158
Hom.:
2426
Cov.:
32
AF XY:
0.168
AC XY:
12533
AN XY:
74400
show subpopulations
Gnomad4 AFR
AF:
0.156
Gnomad4 AMR
AF:
0.113
Gnomad4 ASJ
AF:
0.189
Gnomad4 EAS
AF:
0.00559
Gnomad4 SAS
AF:
0.140
Gnomad4 FIN
AF:
0.195
Gnomad4 NFE
AF:
0.206
Gnomad4 OTH
AF:
0.145
Alfa
AF:
0.191
Hom.:
3172
Bravo
AF:
0.162
Asia WGS
AF:
0.0770
AC:
268
AN:
3478
EpiCase
AF:
0.189
EpiControl
AF:
0.194

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 submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 29, 2016Variant 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
Cadd
Benign
1.1
Dann
Benign
0.52
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs217434; hg19: chr7-44553238; COSMIC: COSV56922474; COSMIC: COSV56922474; API