7-44517233-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001101648.2(NPC1L1):c.3261C>A(p.Asp1087Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1087H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPC1L1 NM_001101648.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.216

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21780413).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1L1	NM_001101648.2	c.3261C>A	p.Asp1087Glu	missense_variant	15/19	ENST00000381160.8
NPC1L1	NM_013389.3	c.3342C>A	p.Asp1114Glu	missense_variant	16/20
NPC1L1	XM_011515326.4	c.3066C>A	p.Asp1022Glu	missense_variant	14/18
NPC1L1	XM_011515328.3	c.1620C>A	p.Asp540Glu	missense_variant	12/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1L1	ENST00000381160.8	c.3261C>A	p.Asp1087Glu	missense_variant	15/19	1	NM_001101648.2	P1
NPC1L1	ENST00000289547.8	c.3342C>A	p.Asp1114Glu	missense_variant	16/20	1
NPC1L1	ENST00000546276.5	c.3123C>A	p.Asp1041Glu	missense_variant	14/18	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2023

The c.3342C>A (p.D1114E) alteration is located in exon 16 (coding exon 16) of the NPC1L1 gene. This alteration results from a C to A substitution at nucleotide position 3342, causing the aspartic acid (D) at amino acid position 1114 to be replaced by a glutamic acid (E). 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	0.24
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	0.70	N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.17	B;.;.
Vest4		0.48
MutPred		0.44		Loss of solvent accessibility (P = 0.0561);.;.;
MVP		0.84
MPC		0.23
ClinPred		0.58	D
GERP RS		0.93
Varity_R		0.049
gMVP		0.30

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: rs778181734; hg19: chr7-44556832;