rs217428

Variant names:

• chr7-44515974-T-G
• rs217428
• NM_001101648.2:c.3634-9A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001101648.2(NPC1L1):​c.3634-9A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,611,844 control chromosomes in the GnomAD database, including 52,495 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (5120 hom., cov: 31)
  • Exomes 𝑓: 0.25 (47375 hom.)
• Consequence: NPC1L1 NM_001101648.2 intron
• Scores: Splicing: ADA: 0.00001679
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.04
• Publications: 11 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 7-44515974-T-G is Benign according to our data. Variant chr7-44515974-T-G is described in ClinVar as Benign. ClinVar VariationId is 403257.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1L1	NM_001101648.2	c.3634-9A>C		intron_variant	Intron 17 of 18	ENST00000381160.8	NP_001095118.1
NPC1L1	NM_013389.3	c.3715-9A>C		intron_variant	Intron 18 of 19		NP_037521.2
NPC1L1	XM_011515326.4	c.3439-9A>C		intron_variant	Intron 16 of 17		XP_011513628.1
NPC1L1	XM_011515328.3	c.1993-9A>C		intron_variant	Intron 14 of 15		XP_011513630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1L1	ENST00000381160.8	c.3634-9A>C		intron_variant	Intron 17 of 18	1	NM_001101648.2	ENSP00000370552.3
NPC1L1	ENST00000289547.8	c.3715-9A>C		intron_variant	Intron 18 of 19	1		ENSP00000289547.4
NPC1L1	ENST00000546276.5	c.3496-9A>C		intron_variant	Intron 16 of 17	1		ENSP00000438033.1

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37798 AN: 151122 Hom.: 5105 Cov.: 31

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.00584

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.214

GnomAD2 exomes AF: 0.211 AC: 52338 AN: 247858 AF XY: 0.212

Gnomad AFR exome AF: 0.292

Gnomad AMR exome AF: 0.110

Gnomad ASJ exome AF: 0.253

Gnomad EAS exome AF: 0.00256

Gnomad FIN exome AF: 0.289

Gnomad NFE exome AF: 0.260

Gnomad OTH exome AF: 0.224

GnomAD4 exome AF: 0.248 AC: 361547 AN: 1460606 Hom.: 47375 Cov.: 38 AF XY: 0.245 AC XY: 177826 AN XY: 726524

African (AFR) AF: 0.301 AC: 10071 AN: 33456

American (AMR) AF: 0.117 AC: 5201 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 6711 AN: 26116

East Asian (EAS) AF: 0.00446 AC: 177 AN: 39688

South Asian (SAS) AF: 0.167 AC: 14348 AN: 86168

European-Finnish (FIN) AF: 0.287 AC: 15308 AN: 53288

Middle Eastern (MID) AF: 0.196 AC: 1129 AN: 5768

European-Non Finnish (NFE) AF: 0.265 AC: 294036 AN: 1111194

Other (OTH) AF: 0.241 AC: 14566 AN: 60344

GnomAD4 genome AF: 0.250 AC: 37850 AN: 151238 Hom.: 5120 Cov.: 31 AF XY: 0.247 AC XY: 18209 AN XY: 73856

African (AFR) AF: 0.294 AC: 12113 AN: 41162

American (AMR) AF: 0.153 AC: 2321 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 923 AN: 3468

East Asian (EAS) AF: 0.00585 AC: 30 AN: 5124

South Asian (SAS) AF: 0.150 AC: 712 AN: 4736

European-Finnish (FIN) AF: 0.298 AC: 3121 AN: 10482

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.266 AC: 17998 AN: 67774

Other (OTH) AF: 0.211 AC: 441 AN: 2090

Alfa AF: 0.263 Hom.: 2369

Bravo AF: 0.239

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.2
DANN	Benign	0.40
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.13		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: rs217428; hg19: chr7-44555573; COSMIC: COSV56922725; COSMIC: COSV56922725;