7-44532058-G-A

Variant names:

• chr7-44532058-G-A
• rs55837134
• NM_001101648.2:c.2547+22C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 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=-0.92).
• 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 rank	MANE	Protein	UniProt
NPC1L1	NM_001101648.2	c.2547+22C>T		intron_variant	Intron 9 of 18	ENST00000381160.8	NP_001095118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1L1	ENST00000381160.8	c.2547+22C>T		intron_variant	Intron 9 of 18	1	NM_001101648.2	ENSP00000370552.3
NPC1L1	ENST00000289547.8	c.2547+22C>T		intron_variant	Intron 9 of 19	1		ENSP00000289547.4
NPC1L1	ENST00000546276.5	c.2547+22C>T		intron_variant	Intron 9 of 17	1		ENSP00000438033.1

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

GnomAD2 exomes AF: 0.133 AC: 33270 AN: 250816 AF XY: 0.135

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 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

African (AFR) AF: 0.0362 AC: 1213 AN: 33480

American (AMR) AF: 0.0671 AC: 3002 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 4539 AN: 26132

East Asian (EAS) AF: 0.00335 AC: 133 AN: 39698

South Asian (SAS) AF: 0.113 AC: 9760 AN: 86256

European-Finnish (FIN) AF: 0.235 AC: 12534 AN: 53382

Middle Eastern (MID) AF: 0.123 AC: 712 AN: 5768

European-Non Finnish (NFE) AF: 0.172 AC: 190905 AN: 1111868

Other (OTH) AF: 0.147 AC: 8881 AN: 60392

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

African (AFR) AF: 0.0411 AC: 1709 AN: 41562

American (AMR) AF: 0.0766 AC: 1172 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 634 AN: 3466

East Asian (EAS) AF: 0.00541 AC: 28 AN: 5178

South Asian (SAS) AF: 0.100 AC: 484 AN: 4824

European-Finnish (FIN) AF: 0.247 AC: 2612 AN: 10578

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.176 AC: 11941 AN: 67962

Other (OTH) AF: 0.106 AC: 223 AN: 2110

Alfa AF: 0.119 Hom.: 454

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
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs55837134; hg19: chr7-44571657;