rs11763759

Variant names:

• chr7-44530468-T-C
• rs11763759
• NM_001101648.2:c.2637+1287A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001101648.2(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 NM_001101648.2 intron
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -0.327
• Publications: 12 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001101648.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1L1	NM_001101648.2	MANE Select	c.2637+1287A>G		intron	N/A	NP_001095118.1	A0A0C4DFX6
	NPC1L1	NM_013389.3		c.2637+1287A>G		intron	N/A	NP_037521.2	Q9UHC9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1L1	ENST00000381160.8	TSL:1 MANE Select	c.2637+1287A>G		intron	N/A	ENSP00000370552.3	A0A0C4DFX6
	NPC1L1	ENST00000289547.8	TSL:1	c.2637+1287A>G		intron	N/A	ENSP00000289547.4	Q9UHC9-1
	NPC1L1	ENST00000546276.5	TSL:1	c.2547+1612A>G		intron	N/A	ENSP00000438033.1	A0A0C4DGG6

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31535 AN: 152036 Hom.: 4226 Cov.: 32

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.: 32 AF XY: 0.203 AC XY: 15079 AN XY: 74392

African (AFR) AF: 0.0561 AC: 2329 AN: 41536

American (AMR) AF: 0.210 AC: 3201 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 952 AN: 3470

East Asian (EAS) AF: 0.0378 AC: 196 AN: 5190

South Asian (SAS) AF: 0.229 AC: 1106 AN: 4828

European-Finnish (FIN) AF: 0.227 AC: 2395 AN: 10570

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.301 AC: 20449 AN: 67964

Other (OTH) AF: 0.235 AC: 496 AN: 2114

Alfa AF: 0.272 Hom.: 8308

Bravo AF: 0.199

Asia WGS AF: 0.137 AC: 477 AN: 3478

ClinVar

ClinVar submissions

Significance: drug response

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Statins, attenuated cholesterol lowering by (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.2
DANN	Benign	0.96
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs11763759;

hg19: chr7-44570067;

COSMIC: COSV56928350;

COSMIC: COSV56928350;