7-44516876-G-T

Variant summary

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

The NM_001101648.2(NPC1L1):c.3346C>A(p.Leu1116Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NPC1L1 NM_001101648.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1L1	NM_001101648.2	c.3346C>A	p.Leu1116Ile	missense_variant	16/19	ENST00000381160.8
NPC1L1	NM_013389.3	c.3427C>A	p.Leu1143Ile	missense_variant	17/20
NPC1L1	XM_011515326.4	c.3151C>A	p.Leu1051Ile	missense_variant	15/18
NPC1L1	XM_011515328.3	c.1705C>A	p.Leu569Ile	missense_variant	13/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1L1	ENST00000381160.8	c.3346C>A	p.Leu1116Ile	missense_variant	16/19	1	NM_001101648.2	P1
NPC1L1	ENST00000289547.8	c.3427C>A	p.Leu1143Ile	missense_variant	17/20	1
NPC1L1	ENST00000546276.5	c.3208C>A	p.Leu1070Ile	missense_variant	15/18	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461820 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jul 25, 2023

The c.3427C>A (p.L1143I) alteration is located in exon 17 (coding exon 17) of the NPC1L1 gene. This alteration results from a C to A substitution at nucleotide position 3427, causing the leucine (L) at amino acid position 1143 to be replaced by an isoleucine (I). 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	0.13
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T;T;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.085	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.0	L;.;.
MutationTaster	Benign	0.64	D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.082	T;T;D
Sift4G	Benign	0.12	T;T;T
Vest4		0.53
MutPred		0.51		Gain of catalytic residue at L1145 (P = 0.3628);.;.;
MVP		0.90
MPC		0.58
ClinPred		0.83	D
GERP RS		4.2
Varity_R		0.095
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs552498840; hg19: chr7-44556475;