7-44539581-G-C

Position:

• chr7-44539581-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001101648.2(NPC1L1):​c.816C>G​(p.Leu272Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,613,858 control chromosomes in the GnomAD database, including 45,308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (4483 hom., cov: 33)
  • Exomes 𝑓: 0.23 (40825 hom.)
• Consequence: NPC1L1 NM_001101648.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1 O: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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-44539581-G-C is Benign according to our data. Variant chr7-44539581-G-C is described in ClinVar as [Benign]. Clinvar id is 403258.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPC1L1	NM_001101648.2	c.816C>G	p.Leu272Leu	synonymous_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.816C>G	p.Leu272Leu	synonymous_variant	2/19	1	NM_001101648.2	ENSP00000370552.3
NPC1L1	ENST00000289547.8	c.816C>G	p.Leu272Leu	synonymous_variant	2/20	1		ENSP00000289547.4
NPC1L1	ENST00000546276.5	c.816C>G	p.Leu272Leu	synonymous_variant	2/18	1		ENSP00000438033.1
NPC1L1	ENST00000423141.1	c.816C>G	p.Leu272Leu	synonymous_variant	2/7	1		ENSP00000404670.1

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35859 AN: 152028 Hom.: 4472 Cov.: 33

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.375

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.206

GnomAD3 exomes AF: 0.249 AC: 62483 AN: 250938 Hom.: 8143 AF XY: 0.245 AC XY: 33205 AN XY: 135688

Gnomad AFR exome AF: 0.209

Gnomad AMR exome AF: 0.254

Gnomad ASJ exome AF: 0.204

Gnomad EAS exome AF: 0.364

Gnomad SAS exome AF: 0.207

Gnomad FIN exome AF: 0.369

Gnomad NFE exome AF: 0.228

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.232 AC: 339457 AN: 1461712 Hom.: 40825 Cov.: 40 AF XY: 0.231 AC XY: 168147 AN XY: 727134

Gnomad4 AFR exome AF: 0.212

Gnomad4 AMR exome AF: 0.249

Gnomad4 ASJ exome AF: 0.211

Gnomad4 EAS exome AF: 0.374

Gnomad4 SAS exome AF: 0.206

Gnomad4 FIN exome AF: 0.359

Gnomad4 NFE exome AF: 0.224

Gnomad4 OTH exome AF: 0.232

GnomAD4 genome AF: 0.236 AC: 35902 AN: 152146 Hom.: 4483 Cov.: 33 AF XY: 0.244 AC XY: 18129 AN XY: 74364

Gnomad4 AFR AF: 0.206

Gnomad4 AMR AF: 0.228

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.375

Gnomad4 SAS AF: 0.214

Gnomad4 FIN AF: 0.368

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.211

Alfa AF: 0.231 Hom.: 3184

Bravo AF: 0.225

Asia WGS AF: 0.298 AC: 1035 AN: 3478

EpiCase AF: 0.214

EpiControl AF: 0.219

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Statins, attenuated cholesterol lowering by Other:1

drug response, no assertion criteria provided

research

Department of Cardiology, Chinese Academy of Medical Sciences, Fuwai Hospital

Nov 01, 2022

- likely responsive

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.5
DANN	Benign	0.43

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: rs2072183; hg19: chr7-44579180; COSMIC: COSV56923068;