7-44513605-C-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.3841G>A(p.Glu1281Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000589 in 1,613,758 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: NPC1L1 NM_001101648.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0660

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=0.0058597326).
• BP6: Variant 7-44513605-C-T is Benign according to our data. Variant chr7-44513605-C-T is described in ClinVar as [Benign]. Clinvar id is 3035704.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1L1	NM_001101648.2	c.3841G>A	p.Glu1281Lys	missense_variant	19/19	ENST00000381160.8
NPC1L1	NM_013389.3	c.3922G>A	p.Glu1308Lys	missense_variant	20/20
NPC1L1	XM_011515326.4	c.3646G>A	p.Glu1216Lys	missense_variant	18/18
NPC1L1	XM_011515328.3	c.2200G>A	p.Glu734Lys	missense_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1L1	ENST00000381160.8	c.3841G>A	p.Glu1281Lys	missense_variant	19/19	1	NM_001101648.2	P1
NPC1L1	ENST00000289547.8	c.3922G>A	p.Glu1308Lys	missense_variant	20/20	1
NPC1L1	ENST00000546276.5	c.3703G>A	p.Glu1235Lys	missense_variant	18/18	1

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 456 AN: 152212 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.000871 AC: 217 AN: 249164 Hom.: 1 AF XY: 0.000608 AC XY: 82 AN XY: 134872

Gnomad AFR exome AF: 0.0116

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000897

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000339 AC: 495 AN: 1461428 Hom.: 1 Cov.: 30 AF XY: 0.000263 AC XY: 191 AN XY: 727022

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.00299 AC: 456 AN: 152330 Hom.: 5 Cov.: 32 AF XY: 0.00306 AC XY: 228 AN XY: 74488

Gnomad4 AFR AF: 0.0102

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.000487 Hom.: 0

Bravo AF: 0.00356

ESP6500AA AF: 0.0107 AC: 47

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000972 AC: 118

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NPC1L1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	6.6
Dann	Benign	0.84
DEOGEN2	Benign	0.074	T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.69	T;T;T
MetaRNN	Benign	0.0059	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.79	N;N;N
REVEL	Benign	0.052
Sift	Benign	0.80	T;T;T
Sift4G	Benign	0.23	T;T;T
Vest4		0.059
MVP		0.55
MPC		0.17
ClinPred		0.00088	T
GERP RS		-0.69
Varity_R		0.041
gMVP		0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs217435; hg19: chr7-44553204; COSMIC: COSV99204286; COSMIC: COSV99204286;