7-44513639-A-G

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.3807T>C(p.Val1269=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,612,656 control chromosomes in the GnomAD database, including 29,821 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.17 (2426 hom., cov: 32)
  • Exomes 𝑓: 0.19 (27395 hom.)
• Consequence: NPC1L1 NM_001101648.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.508

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=-0.81).
• BP6: Variant 7-44513639-A-G is Benign according to our data. Variant chr7-44513639-A-G is described in ClinVar as [Benign]. Clinvar id is 403255.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.508 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1L1	NM_001101648.2	c.3807T>C	p.Val1269=	synonymous_variant	19/19	ENST00000381160.8
NPC1L1	NM_013389.3	c.3888T>C	p.Val1296=	synonymous_variant	20/20
NPC1L1	XM_011515326.4	c.3612T>C	p.Val1204=	synonymous_variant	18/18
NPC1L1	XM_011515328.3	c.2166T>C	p.Val722=	synonymous_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1L1	ENST00000381160.8	c.3807T>C	p.Val1269=	synonymous_variant	19/19	1	NM_001101648.2	P1
NPC1L1	ENST00000289547.8	c.3888T>C	p.Val1296=	synonymous_variant	20/20	1
NPC1L1	ENST00000546276.5	c.3669T>C	p.Val1223=	synonymous_variant	18/18	1

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26083 AN: 152040 Hom.: 2419 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.00558

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.148

GnomAD3 exomes AF: 0.159 AC: 39467 AN: 248704 Hom.: 3754 AF XY: 0.163 AC XY: 21883 AN XY: 134658

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.0778

Gnomad ASJ exome AF: 0.190

Gnomad EAS exome AF: 0.00239

Gnomad SAS exome AF: 0.156

Gnomad FIN exome AF: 0.195

Gnomad NFE exome AF: 0.201

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.189 AC: 275342 AN: 1460498 Hom.: 27395 Cov.: 33 AF XY: 0.188 AC XY: 136616 AN XY: 726590

Gnomad4 AFR exome AF: 0.162

Gnomad4 AMR exome AF: 0.0825

Gnomad4 ASJ exome AF: 0.192

Gnomad4 EAS exome AF: 0.00416

Gnomad4 SAS exome AF: 0.162

Gnomad4 FIN exome AF: 0.194

Gnomad4 NFE exome AF: 0.202

Gnomad4 OTH exome AF: 0.182

GnomAD4 genome AF: 0.172 AC: 26110 AN: 152158 Hom.: 2426 Cov.: 32 AF XY: 0.168 AC XY: 12533 AN XY: 74400

Gnomad4 AFR AF: 0.156

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.189

Gnomad4 EAS AF: 0.00559

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.195

Gnomad4 NFE AF: 0.206

Gnomad4 OTH AF: 0.145

Alfa AF: 0.191 Hom.: 3172

Bravo AF: 0.162

Asia WGS AF: 0.0770 AC: 268 AN: 3478

EpiCase AF: 0.189

EpiControl AF: 0.194

ClinVar

Significance: Benign

Submissions summary: Benign: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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	1.1
Dann	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs217434; hg19: chr7-44553238; COSMIC: COSV56922474; COSMIC: COSV56922474;