7-44541277-G-T

Variant names:

• chr7-44541277-G-T
• rs41279633
• NM_001101648.2:c.-18C>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 41 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=-0.79).
• 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 rank	MANE	Protein	UniProt
NPC1L1	NM_001101648.2	c.-18C>A		5_prime_UTR_variant	Exon 1 of 19	ENST00000381160.8	NP_001095118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1L1	ENST00000381160.8	c.-18C>A		5_prime_UTR_variant	Exon 1 of 19	1	NM_001101648.2	ENSP00000370552.3
NPC1L1	ENST00000289547.8	c.-18C>A		5_prime_UTR_variant	Exon 1 of 20	1		ENSP00000289547.4
NPC1L1	ENST00000546276.5	c.-18C>A		5_prime_UTR_variant	Exon 1 of 18	1		ENSP00000438033.1
NPC1L1	ENST00000423141.1	c.-18C>A		5_prime_UTR_variant	Exon 1 of 7	1		ENSP00000404670.1

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

GnomAD2 exomes AF: 0.120 AC: 17517 AN: 145864 AF XY: 0.120

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 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

African (AFR) AF: 0.0255 AC: 806 AN: 31578

American (AMR) AF: 0.0639 AC: 2278 AN: 35664

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 3932 AN: 25128

East Asian (EAS) AF: 0.0132 AC: 473 AN: 35724

South Asian (SAS) AF: 0.103 AC: 8141 AN: 79130

European-Finnish (FIN) AF: 0.213 AC: 10122 AN: 47540

Middle Eastern (MID) AF: 0.118 AC: 659 AN: 5572

European-Non Finnish (NFE) AF: 0.156 AC: 168512 AN: 1077942

Other (OTH) AF: 0.133 AC: 7730 AN: 57924

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

African (AFR) AF: 0.0303 AC: 1260 AN: 41578

American (AMR) AF: 0.0760 AC: 1163 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 594 AN: 3470

East Asian (EAS) AF: 0.0210 AC: 109 AN: 5182

South Asian (SAS) AF: 0.0920 AC: 444 AN: 4828

European-Finnish (FIN) AF: 0.221 AC: 2344 AN: 10606

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11052 AN: 67994

Other (OTH) AF: 0.101 AC: 213 AN: 2116

Alfa AF: 0.0917 Hom.: 274

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
PhyloP100		0.091
PromoterAI		0.12	Neutral
Mutation Taster		=300/0	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

Other links and lift over

dbSNP: rs41279633; hg19: chr7-44580876;