rs52815063

Variant names:

• chr7-44516100-A-T
• rs52815063
• NM_001101648.2:c.3617T>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001101648.2(NPC1L1):​c.3617T>A​(p.Ile1206Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0117 in 1,612,224 control chromosomes in the GnomAD database, including 148 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (7 hom., cov: 32)
  • Exomes 𝑓: 0.012 (141 hom.)
• Consequence: NPC1L1 NM_001101648.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 3.96
• Publications: 14 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073070824).
• BP6: Variant 7-44516100-A-T is Benign according to our data. Variant chr7-44516100-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

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.3617T>A	p.Ile1206Asn	missense	Exon 17 of 19	NP_001095118.1
	NPC1L1	NM_013389.3		c.3698T>A	p.Ile1233Asn	missense	Exon 18 of 20	NP_037521.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1L1	ENST00000381160.8	TSL:1 MANE Select	c.3617T>A	p.Ile1206Asn	missense	Exon 17 of 19	ENSP00000370552.3
	NPC1L1	ENST00000289547.8	TSL:1	c.3698T>A	p.Ile1233Asn	missense	Exon 18 of 20	ENSP00000289547.4
	NPC1L1	ENST00000546276.5	TSL:1	c.3479T>A	p.Ile1160Asn	missense	Exon 16 of 18	ENSP00000438033.1

Frequencies

GnomAD3 genomes AF: 0.00777 AC: 1183 AN: 152156 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00787 AC: 1946 AN: 247116 AF XY: 0.00772

Gnomad AFR exome AF: 0.00158

Gnomad AMR exome AF: 0.00331

Gnomad ASJ exome AF: 0.00935

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.0154

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.00545

GnomAD4 exome AF: 0.0122 AC: 17758 AN: 1459950 Hom.: 141 Cov.: 33 AF XY: 0.0118 AC XY: 8547 AN XY: 726084

African (AFR) AF: 0.00191 AC: 64 AN: 33466

American (AMR) AF: 0.00324 AC: 144 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.0102 AC: 265 AN: 26042

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39674

South Asian (SAS) AF: 0.00284 AC: 244 AN: 85820

European-Finnish (FIN) AF: 0.0150 AC: 800 AN: 53284

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.0140 AC: 15512 AN: 1111136

Other (OTH) AF: 0.0120 AC: 724 AN: 60324

GnomAD4 genome AF: 0.00777 AC: 1183 AN: 152274 Hom.: 7 Cov.: 32 AF XY: 0.00743 AC XY: 553 AN XY: 74452

African (AFR) AF: 0.00238 AC: 99 AN: 41554

American (AMR) AF: 0.00373 AC: 57 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.0162 AC: 172 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0119 AC: 807 AN: 68024

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.0106 Hom.: 4

Bravo AF: 0.00669

TwinsUK AF: 0.0154 AC: 57

ALSPAC AF: 0.0161 AC: 62

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0135 AC: 116

ExAC AF: 0.00759 AC: 921

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely 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 in ESP (all): 124/13006=0.95%; In EUR: 116/8600=1.34%

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Ezetimibe response Other:1

Feb 01, 2005

OMIM

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.74	N
PhyloP100		4.0
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.27
Sift	Benign	0.038	D
Sift4G	Benign	0.083	T
Vest4		0.59
MVP		0.80
MPC		0.59
ClinPred		0.032	T
GERP RS		4.3
Varity_R		0.30
gMVP		0.71
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs52815063; hg19: chr7-44555699;