7-44517235-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_001101648.2(NPC1L1):c.3259G>T(p.Asp1087Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,613,838 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1087E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

NPC1L1
NM_001101648.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.67

Variant links:

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]

NPC1L1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NPC1L1	NM_001101648.2 linkuse as main transcript	c.3259G>T	p.Asp1087Tyr	missense_variant	15/19	ENST00000381160.8
NPC1L1	NM_013389.3 linkuse as main transcript	c.3340G>T	p.Asp1114Tyr	missense_variant	16/20
NPC1L1	XM_011515326.4 linkuse as main transcript	c.3064G>T	p.Asp1022Tyr	missense_variant	14/18
NPC1L1	XM_011515328.3 linkuse as main transcript	c.1618G>T	p.Asp540Tyr	missense_variant	12/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1L1	ENST00000381160.8 linkuse as main transcript	c.3259G>T	p.Asp1087Tyr	missense_variant	15/19	1	NM_001101648.2	P1
NPC1L1	ENST00000289547.8 linkuse as main transcript	c.3340G>T	p.Asp1114Tyr	missense_variant	16/20	1			Q9UHC9-1
NPC1L1	ENST00000546276.5 linkuse as main transcript	c.3121G>T	p.Asp1041Tyr	missense_variant	14/18	1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

151984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00144

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:

0.00

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251424

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000424

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00161

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000526

AC:

AN:

151984

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74232

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000338

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2023

The c.3340G>T (p.D1114Y) alteration is located in exon 16 (coding exon 16) of the NPC1L1 gene. This alteration results from a G to T substitution at nucleotide position 3340, causing the aspartic acid (D) at amino acid position 1114 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Uncertain

-0.020

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.57

D;T;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.46

T;T;T

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

1.9

L;.;.

MutationTaster

Benign

0.95

D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.3

D;D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.0060

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

0.99

D;.;.

Vest4

0.70

MutPred

0.56

Loss of solvent accessibility (P = 0.0152);.;.;

MVP

0.88

MPC

0.71

ClinPred

0.73

GERP RS

5.3

Varity_R

0.29

gMVP

0.67

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over