7-44539868-C-T

Position:

• chr7-44539868-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001101648.2(NPC1L1):​c.529G>A​(p.Val177Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00422 in 1,614,024 control chromosomes in the GnomAD database, including 98 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (88 hom.)
• Consequence: NPC1L1 NM_001101648.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.115

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068393946).
• BP6: Variant 7-44539868-C-T is Benign according to our data. Variant chr7-44539868-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1L1	NM_001101648.2	c.529G>A	p.Val177Ile	missense_variant	2/19	ENST00000381160.8	NP_001095118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPC1L1	ENST00000381160.8	c.529G>A	p.Val177Ile	missense_variant	2/19	1	NM_001101648.2	ENSP00000370552.3
NPC1L1	ENST00000289547.8	c.529G>A	p.Val177Ile	missense_variant	2/20	1		ENSP00000289547.4
NPC1L1	ENST00000546276.5	c.529G>A	p.Val177Ile	missense_variant	2/18	1		ENSP00000438033.1
NPC1L1	ENST00000423141.1	c.529G>A	p.Val177Ile	missense_variant	2/7	1		ENSP00000404670.1

Frequencies

GnomAD3 genomes AF: 0.00596 AC: 907 AN: 152184 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0312

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00797

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00635 AC: 1594 AN: 250844 Hom.: 28 AF XY: 0.00607 AC XY: 823 AN XY: 135588

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00259

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0321

Gnomad NFE exome AF: 0.00718

Gnomad OTH exome AF: 0.00669

GnomAD4 exome AF: 0.00404 AC: 5909 AN: 1461722 Hom.: 88 Cov.: 34 AF XY: 0.00411 AC XY: 2989 AN XY: 727164

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00272

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0323

Gnomad4 NFE exome AF: 0.00348

Gnomad4 OTH exome AF: 0.00338

GnomAD4 genome AF: 0.00596 AC: 907 AN: 152302 Hom.: 10 Cov.: 32 AF XY: 0.00655 AC XY: 488 AN XY: 74468

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0312

Gnomad4 NFE AF: 0.00797

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00736 Hom.: 9

Bravo AF: 0.00247

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00593 AC: 51

ExAC AF: 0.00659 AC: 800

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00344

EpiControl AF: 0.00332

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 14, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	NPC1L1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.017
DANN	Benign	0.32
DEOGEN2	Benign	0.30	T;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.49	T;T;T;T
MetaRNN	Benign	0.0068	T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	-1.3	N;.;.;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.070	N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.98	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0010	.;.;.;B
Vest4		0.066
MVP		0.64
MPC		0.12
ClinPred		0.0028	T
GERP RS		-0.21
Varity_R		0.10
gMVP		0.33

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: rs149017550; hg19: chr7-44579467;