rs55837134

chr7-44532058-G-Achr7-44532058-G-Cchr7-44532058-G-T

Variant summary

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

The NM_001101648.2(NPC1L1):c.2547+22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,613,884 control chromosomes in the GnomAD database, including 21,535 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 0.12 (1580 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19955 hom.)
• Consequence: NPC1L1 NM_001101648.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.23

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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1L1	NM_001101648.2	c.2547+22C>T		intron_variant		ENST00000381160.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1L1	ENST00000381160.8	c.2547+22C>T		intron_variant		1	NM_001101648.2	P1
NPC1L1	ENST00000289547.8	c.2547+22C>T		intron_variant		1
NPC1L1	ENST00000546276.5	c.2547+22C>T		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.125 AC: 18933 AN: 152066 Hom.: 1579 Cov.: 32

Gnomad AFR AF: 0.0412

Gnomad AMI AF: 0.0989

Gnomad AMR AF: 0.0768

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.00539

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.107

GnomAD3 exomes AF: 0.133 AC: 33270 AN: 250816 Hom.: 2881 AF XY: 0.135 AC XY: 18385 AN XY: 135722

Gnomad AFR exome AF: 0.0362

Gnomad AMR exome AF: 0.0641

Gnomad ASJ exome AF: 0.175

Gnomad EAS exome AF: 0.00120

Gnomad SAS exome AF: 0.109

Gnomad FIN exome AF: 0.241

Gnomad NFE exome AF: 0.170

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.159 AC: 231679 AN: 1461700 Hom.: 19955 Cov.: 34 AF XY: 0.158 AC XY: 114539 AN XY: 727162

Gnomad4 AFR exome AF: 0.0362

Gnomad4 AMR exome AF: 0.0671

Gnomad4 ASJ exome AF: 0.174

Gnomad4 EAS exome AF: 0.00335

Gnomad4 SAS exome AF: 0.113

Gnomad4 FIN exome AF: 0.235

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.147

GnomAD4 genome AF: 0.124 AC: 18926 AN: 152184 Hom.: 1580 Cov.: 32 AF XY: 0.125 AC XY: 9325 AN XY: 74424

Gnomad4 AFR AF: 0.0411

Gnomad4 AMR AF: 0.0766

Gnomad4 ASJ AF: 0.183

Gnomad4 EAS AF: 0.00541

Gnomad4 SAS AF: 0.100

Gnomad4 FIN AF: 0.247

Gnomad4 NFE AF: 0.176

Gnomad4 OTH AF: 0.106

Alfa AF: 0.116 Hom.: 245

Bravo AF: 0.106

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.079
Dann	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs55837134; hg19: chr7-44571657;