rs217430

Positions:

• chr7-44515482-A-G

Variant summary

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

The NM_001101648.2(NPC1L1):​c.3796+321T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 152,178 control chromosomes in the GnomAD database, including 3,425 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 0.20 (3425 hom., cov: 32)
• Consequence: NPC1L1 NM_001101648.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34

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=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1L1	NM_001101648.2	c.3796+321T>C		intron_variant		ENST00000381160.8	NP_001095118.1
NPC1L1	NM_013389.3	c.3877+321T>C		intron_variant			NP_037521.2
NPC1L1	XM_011515326.4	c.3601+321T>C		intron_variant			XP_011513628.1
NPC1L1	XM_011515328.3	c.2155+321T>C		intron_variant			XP_011513630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC1L1	ENST00000381160.8	c.3796+321T>C		intron_variant		1	NM_001101648.2	ENSP00000370552	P1
NPC1L1	ENST00000289547.8	c.3877+321T>C		intron_variant		1		ENSP00000289547
NPC1L1	ENST00000546276.5	c.3658+321T>C		intron_variant		1		ENSP00000438033

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30840 AN: 152060 Hom.: 3419 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.00615

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.168

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

GnomAD4 genome AF: 0.203 AC: 30869 AN: 152178 Hom.: 3425 Cov.: 32 AF XY: 0.201 AC XY: 14955 AN XY: 74402

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.133

Gnomad4 ASJ AF: 0.244

Gnomad4 EAS AF: 0.00617

Gnomad4 SAS AF: 0.143

Gnomad4 FIN AF: 0.289

Gnomad4 NFE AF: 0.246

Gnomad4 OTH AF: 0.165

Alfa AF: 0.226 Hom.: 8207

Bravo AF: 0.188

Asia WGS AF: 0.0800 AC: 279 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.072
DANN	Benign	0.63

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: rs217430; hg19: chr7-44555081;