7-44515482-A-G

Variant names:

• chr7-44515482-A-G
• rs217430
• NM_001101648.2:c.3796+321T>C

Variant summary

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

The NM_001101648.2(NPC1L1):​c.3796+321T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 152,178 control chromosomes in the GnomAD database, including 3,425 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 0.20 (3425 hom., cov: 32)
• Consequence: NPC1L1 NM_001101648.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34
• Publications: 8 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=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1L1	NM_001101648.2	c.3796+321T>C		intron_variant	Intron 18 of 18	ENST00000381160.8	NP_001095118.1
NPC1L1	NM_013389.3	c.3877+321T>C		intron_variant	Intron 19 of 19		NP_037521.2
NPC1L1	XM_011515326.4	c.3601+321T>C		intron_variant	Intron 17 of 17		XP_011513628.1
NPC1L1	XM_011515328.3	c.2155+321T>C		intron_variant	Intron 15 of 15		XP_011513630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1L1	ENST00000381160.8	c.3796+321T>C		intron_variant	Intron 18 of 18	1	NM_001101648.2	ENSP00000370552.3
NPC1L1	ENST00000289547.8	c.3877+321T>C		intron_variant	Intron 19 of 19	1		ENSP00000289547.4
NPC1L1	ENST00000546276.5	c.3658+321T>C		intron_variant	Intron 17 of 17	1		ENSP00000438033.1

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30840 AN: 152060 Hom.: 3419 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.00615

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.168

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.203 AC: 30869 AN: 152178 Hom.: 3425 Cov.: 32 AF XY: 0.201 AC XY: 14955 AN XY: 74402

African (AFR) AF: 0.168 AC: 6978 AN: 41504

American (AMR) AF: 0.133 AC: 2027 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 848 AN: 3472

East Asian (EAS) AF: 0.00617 AC: 32 AN: 5188

South Asian (SAS) AF: 0.143 AC: 688 AN: 4820

European-Finnish (FIN) AF: 0.289 AC: 3053 AN: 10576

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

European-Non Finnish (NFE) AF: 0.246 AC: 16715 AN: 68002

Other (OTH) AF: 0.165 AC: 349 AN: 2112

Alfa AF: 0.221 Hom.: 12408

Bravo AF: 0.188

Asia WGS AF: 0.0800 AC: 279 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.072
DANN	Benign	0.63
PhyloP100		-1.3
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: rs217430; hg19: chr7-44555081;