Variant 7-44530468-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000381160.8(NPC1L1):c.2637+1287A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 152,154 control chromosomes in the GnomAD database, including 4,225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

Frequency

Genomes: 𝑓 0.21 ( 4225 hom., cov: 32)

Consequence

NPC1L1
ENST00000381160.8 intron

Scores

Clinical Significance

drug response no assertion criteria provided O:1

Conservation

PhyloP100: -0.327

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]

NPC1L1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1L1	NM_001101648.2 linkuse as main transcript	c.2637+1287A>G		intron_variant		ENST00000381160.8	NP_001095118.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
NPC1L1	ENST00000381160.8 linkuse as main transcript	c.2637+1287A>G	intron_variant	1	NM_001101648.2	ENSP00000370552	P1
NPC1L1	ENST00000289547.8 linkuse as main transcript	c.2637+1287A>G	intron_variant	1		ENSP00000289547		Q9UHC9-1
NPC1L1	ENST00000546276.5 linkuse as main transcript	c.2547+1612A>G	intron_variant	1		ENSP00000438033

Frequencies

GnomAD3 genomes

AF:

0.207

AC:

31535

AN:

152036

Hom.:

4226

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0562

Gnomad AMI

AF:

0.364

Gnomad AMR

AF:

0.210

Gnomad ASJ

AF:

0.274

Gnomad EAS

AF:

0.0377

Gnomad SAS

AF:

0.230

Gnomad FIN

AF:

0.227

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.301

Gnomad OTH

AF:

0.236

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.207

AC:

31525

AN:

152154

Hom.:

4225

Cov.:

AF XY:

0.203

AC XY:

15079

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0561

Gnomad4 AMR

AF:

0.210

Gnomad4 ASJ

AF:

0.274

Gnomad4 EAS

AF:

0.0378

Gnomad4 SAS

AF:

0.229

Gnomad4 FIN

AF:

0.227

Gnomad4 NFE

AF:

0.301

Gnomad4 OTH

AF:

0.235

Alfa

AF:

0.279

Hom.:

6397

Bravo

AF:

0.199

Asia WGS

AF:

0.137

AC:

477

AN:

3478

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Statins, attenuated cholesterol lowering by

Other:1

drug response, no assertion criteria provided

research

Department of Cardiology, Chinese Academy of Medical Sciences, Fuwai Hospital

Nov 01, 2022

- likely responsive

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

7.2

DANN

Benign

0.96

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over