rs3187907

Positions:

• chr7-44512610-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001101648.2(NPC1L1):​c.*837A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 152,442 control chromosomes in the GnomAD database, including 1,913 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.14 (1910 hom., cov: 33)
  • Exomes 𝑓: 0.17 (3 hom.)
• Consequence: NPC1L1 NM_001101648.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.444

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• 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
NPC1L1	NM_001101648.2	c.*837A>G		3_prime_UTR_variant	19/19	ENST00000381160.8
NPC1L1	NM_013389.3	c.*837A>G		3_prime_UTR_variant	20/20
NPC1L1	XM_011515326.4	c.*837A>G		3_prime_UTR_variant	18/18
NPC1L1	XM_011515328.3	c.*837A>G		3_prime_UTR_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1L1	ENST00000381160.8	c.*837A>G		3_prime_UTR_variant	19/19	1	NM_001101648.2	P1
NPC1L1	ENST00000289547.8	c.*837A>G		3_prime_UTR_variant	20/20	1
NPC1L1	ENST00000546276.5	c.*837A>G		3_prime_UTR_variant	18/18	1

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21119 AN: 152168 Hom.: 1910 Cov.: 33

Gnomad AFR AF: 0.0432

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.0982

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.00558

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.129

GnomAD4 exome AF: 0.167 AC: 26 AN: 156 Hom.: 3 Cov.: 0 AF XY: 0.170 AC XY: 15 AN XY: 88

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.164

Gnomad4 OTH exome AF: 0.750

GnomAD4 genome AF: 0.139 AC: 21115 AN: 152286 Hom.: 1910 Cov.: 33 AF XY: 0.136 AC XY: 10115 AN XY: 74450

Gnomad4 AFR AF: 0.0432

Gnomad4 AMR AF: 0.0979

Gnomad4 ASJ AF: 0.187

Gnomad4 EAS AF: 0.00559

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.195

Gnomad4 NFE AF: 0.205

Gnomad4 OTH AF: 0.126

Alfa AF: 0.181 Hom.: 2610

Bravo AF: 0.124

Asia WGS AF: 0.0660 AC: 230 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.80
DANN	Benign	0.67

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

Other links and lift over

dbSNP: rs3187907; hg19: chr7-44552209;