7-44541392-T-C

Variant names:

• chr7-44541392-T-C
• rs17655652
• NM_001101648.2:c.-133A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001101648.2(NPC1L1):​c.-133A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 759,692 control chromosomes in the GnomAD database, including 31,190 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 0.22 (4712 hom., cov: 33)
  • Exomes 𝑓: 0.28 (26478 hom.)
• Consequence: NPC1L1 NM_001101648.2 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.434
• Publications: 30 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=-0.77).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.312 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001101648.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1L1	NM_001101648.2	MANE Select	c.-133A>G		upstream_gene	N/A	NP_001095118.1
	NPC1L1	NM_013389.3		c.-133A>G		upstream_gene	N/A	NP_037521.2
	NPC1L1	NM_001300967.2		c.-133A>G		upstream_gene	N/A	NP_001287896.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1L1	ENST00000381160.8	TSL:1 MANE Select	c.-133A>G		upstream_gene	N/A	ENSP00000370552.3
	NPC1L1	ENST00000289547.8	TSL:1	c.-133A>G		upstream_gene	N/A	ENSP00000289547.4
	NPC1L1	ENST00000546276.5	TSL:1	c.-133A>G		upstream_gene	N/A	ENSP00000438033.1

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33315 AN: 152094 Hom.: 4712 Cov.: 33

Gnomad AFR AF: 0.0644

Gnomad AMI AF: 0.432

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.00964

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.259

GnomAD4 exome AF: 0.280 AC: 170341 AN: 607480 Hom.: 26478 AF XY: 0.280 AC XY: 87414 AN XY: 312004

African (AFR) AF: 0.0593 AC: 957 AN: 16148

American (AMR) AF: 0.230 AC: 5018 AN: 21820

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 4151 AN: 14900

East Asian (EAS) AF: 0.0121 AC: 383 AN: 31584

South Asian (SAS) AF: 0.249 AC: 12283 AN: 49428

European-Finnish (FIN) AF: 0.235 AC: 7418 AN: 31510

Middle Eastern (MID) AF: 0.295 AC: 1150 AN: 3896

European-Non Finnish (NFE) AF: 0.321 AC: 130715 AN: 406738

Other (OTH) AF: 0.263 AC: 8266 AN: 31456

GnomAD4 genome AF: 0.219 AC: 33313 AN: 152212 Hom.: 4712 Cov.: 33 AF XY: 0.213 AC XY: 15870 AN XY: 74406

African (AFR) AF: 0.0643 AC: 2673 AN: 41550

American (AMR) AF: 0.241 AC: 3688 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 936 AN: 3472

East Asian (EAS) AF: 0.00947 AC: 49 AN: 5176

South Asian (SAS) AF: 0.226 AC: 1092 AN: 4832

European-Finnish (FIN) AF: 0.226 AC: 2395 AN: 10596

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.316 AC: 21471 AN: 67978

Other (OTH) AF: 0.256 AC: 541 AN: 2112

Alfa AF: 0.278 Hom.: 20817

Bravo AF: 0.213

Asia WGS AF: 0.122 AC: 426 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.71
PhyloP100		-0.43
PromoterAI		0.075	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17655652; hg19: chr7-44580991;