7-44541277-G-T

Position:

• chr7-44541277-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.-18C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,548,494 control chromosomes in the GnomAD database, including 17,280 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 0.11 (1328 hom., cov: 32)
  • Exomes 𝑓: 0.15 (15952 hom.)
• Consequence: NPC1L1 NM_001101648.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0910

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=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1L1	NM_001101648.2	c.-18C>A		5_prime_UTR_variant	1/19	ENST00000381160.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1L1	ENST00000381160.8	c.-18C>A		5_prime_UTR_variant	1/19	1	NM_001101648.2	P1
NPC1L1	ENST00000289547.8	c.-18C>A		5_prime_UTR_variant	1/20	1
NPC1L1	ENST00000423141.1	c.-18C>A		5_prime_UTR_variant	1/7	1
NPC1L1	ENST00000546276.5	c.-18C>A		5_prime_UTR_variant	1/18	1

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17340 AN: 152174 Hom.: 1328 Cov.: 32

Gnomad AFR AF: 0.0304

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0762

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.0210

Gnomad SAS AF: 0.0925

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.102

GnomAD3 exomes AF: 0.120 AC: 17517 AN: 145864 Hom.: 1309 AF XY: 0.120 AC XY: 9366 AN XY: 77786

Gnomad AFR exome AF: 0.0277

Gnomad AMR exome AF: 0.0596

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.0219

Gnomad SAS exome AF: 0.0982

Gnomad FIN exome AF: 0.219

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.145 AC: 202653 AN: 1396202 Hom.: 15952 Cov.: 32 AF XY: 0.145 AC XY: 99619 AN XY: 688666

Gnomad4 AFR exome AF: 0.0255

Gnomad4 AMR exome AF: 0.0639

Gnomad4 ASJ exome AF: 0.156

Gnomad4 EAS exome AF: 0.0132

Gnomad4 SAS exome AF: 0.103

Gnomad4 FIN exome AF: 0.213

Gnomad4 NFE exome AF: 0.156

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.114 AC: 17331 AN: 152292 Hom.: 1328 Cov.: 32 AF XY: 0.115 AC XY: 8541 AN XY: 74450

Gnomad4 AFR AF: 0.0303

Gnomad4 AMR AF: 0.0760

Gnomad4 ASJ AF: 0.171

Gnomad4 EAS AF: 0.0210

Gnomad4 SAS AF: 0.0920

Gnomad4 FIN AF: 0.221

Gnomad4 NFE AF: 0.163

Gnomad4 OTH AF: 0.101

Alfa AF: 0.116 Hom.: 269

Bravo AF: 0.0974

Asia WGS AF: 0.0560 AC: 194 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.3
DANN	Benign	0.75

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: rs41279633; hg19: chr7-44580876;