7-44516704-G-A

Position:

chr7-44516704-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001101648.2(NPC1L1):c.3518C>T(p.Ser1173Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000429 in 1,608,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

NPC1L1
NM_001101648.2 missense, splice_region

Scores

Splicing: ADA: 0.9952

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13450783).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1L1	NM_001101648.2 linkuse as main transcript	c.3518C>T	p.Ser1173Leu	missense_variant, splice_region_variant	16/19	ENST00000381160.8	NP_001095118.1	Q9UHC9A0A0C4DFX6
NPC1L1	NM_013389.3 linkuse as main transcript	c.3599C>T	p.Ser1200Leu	missense_variant, splice_region_variant	17/20		NP_037521.2	Q9UHC9-1
NPC1L1	XM_011515326.4 linkuse as main transcript	c.3323C>T	p.Ser1108Leu	missense_variant, splice_region_variant	15/18		XP_011513628.1
NPC1L1	XM_011515328.3 linkuse as main transcript	c.1877C>T	p.Ser626Leu	missense_variant, splice_region_variant	13/16		XP_011513630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NPC1L1	ENST00000381160.8 linkuse as main transcript	c.3518C>T	p.Ser1173Leu	missense_variant, splice_region_variant	16/19	1	NM_001101648.2	ENSP00000370552.3	A0A0C4DFX6
NPC1L1	ENST00000289547.8 linkuse as main transcript	c.3599C>T	p.Ser1200Leu	missense_variant, splice_region_variant	17/20	1		ENSP00000289547.4	Q9UHC9-1
NPC1L1	ENST00000546276.5 linkuse as main transcript	c.3380C>T	p.Ser1127Leu	missense_variant, splice_region_variant	15/18	1		ENSP00000438033.1	A0A0C4DGG6

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000117

AC:

AN:

240154

Hom.:

AF XY:

0.000116

AC XY:

AN XY:

129644

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000509

Gnomad ASJ exome

AF:

0.000102

Gnomad EAS exome

AF:

0.0000565

Gnomad SAS exome

AF:

0.0000340

Gnomad FIN exome

AF:

0.0000488

Gnomad NFE exome

AF:

0.0000647

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000426

AC:

AN:

1455798

Hom.:

Cov.:

AF XY:

0.0000470

AC XY:

AN XY:

723600

show subpopulations

Gnomad4 AFR exome

AF:

0.0000600

Gnomad4 AMR exome

AF:

0.000389

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.0000352

Gnomad4 FIN exome

AF:

0.0000377

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000665

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.0000741

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

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 17, 2024

The c.3599C>T (p.S1200L) alteration is located in exon 17 (coding exon 17) of the NPC1L1 gene. This alteration results from a C to T substitution at nucleotide position 3599, causing the serine (S) at amino acid position 1200 to be replaced by a leucine (L). 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

0.21

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;T;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.032

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

-0.88

N;.;.

PrimateAI

Benign

0.31

PROVEAN

Benign

1.1

N;N;N

REVEL

Benign

0.27

Sift

Benign

0.23

T;T;T

Sift4G

Uncertain

0.010

D;D;D

Vest4

0.43

MVP

0.85

MPC

0.14

ClinPred

0.057

GERP RS

5.2

Varity_R

0.094

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Benign

0.69

SpliceAI score (max)

0.040

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