rs52815063

chr7-44516100-A-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate 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. 13/20 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, single submitter B:1 O:1
• Conservation: PhyloP100: 3.96

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

Verdict is Benign. Variant got -10 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 id is 2621.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-44516100-A-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1L1	NM_001101648.2	c.3617T>A	p.Ile1206Asn	missense_variant	17/19	ENST00000381160.8
NPC1L1	NM_013389.3	c.3698T>A	p.Ile1233Asn	missense_variant	18/20
NPC1L1	XM_011515326.4	c.3422T>A	p.Ile1141Asn	missense_variant	16/18
NPC1L1	XM_011515328.3	c.1976T>A	p.Ile659Asn	missense_variant	14/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1L1	ENST00000381160.8	c.3617T>A	p.Ile1206Asn	missense_variant	17/19	1	NM_001101648.2	P1
NPC1L1	ENST00000289547.8	c.3698T>A	p.Ile1233Asn	missense_variant	18/20	1
NPC1L1	ENST00000546276.5	c.3479T>A	p.Ile1160Asn	missense_variant	16/18	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

GnomAD3 exomes AF: 0.00787 AC: 1946 AN: 247116 Hom.: 17 AF XY: 0.00772 AC XY: 1031 AN XY: 133586

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 SAS exome AF: 0.00243

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

Gnomad4 AFR exome AF: 0.00191

Gnomad4 AMR exome AF: 0.00324

Gnomad4 ASJ exome AF: 0.0102

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00284

Gnomad4 FIN exome AF: 0.0150

Gnomad4 NFE exome AF: 0.0140

Gnomad4 OTH exome AF: 0.0120

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

Gnomad4 AFR AF: 0.00238

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0162

Gnomad4 NFE AF: 0.0119

Gnomad4 OTH AF: 0.00567

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:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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% -

Ezetimibe response Other:1

drug response, no assertion criteria provided

literature only

OMIM

Feb 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

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;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.95	D;D;D
MetaRNN	Benign	0.0073	T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.74	N;.;.
MutationTaster	Benign	0.68	D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.038	D;D;D
Sift4G	Benign	0.083	T;T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs52815063; hg19: chr7-44555699;