7-44515807-G-A

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.3792C>T(p.Tyr1264=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,613,972 control chromosomes in the GnomAD database, including 36,381 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (2531 hom., cov: 32)
  • Exomes 𝑓: 0.21 (33850 hom.)
• Consequence: NPC1L1 NM_001101648.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.25

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=-0.55).
• BP6: Variant 7-44515807-G-A is Benign according to our data. Variant chr7-44515807-G-A is described in ClinVar as [Benign]. Clinvar id is 403256.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.25 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1L1	NM_001101648.2	c.3792C>T	p.Tyr1264=	synonymous_variant	18/19	ENST00000381160.8
NPC1L1	NM_013389.3	c.3873C>T	p.Tyr1291=	synonymous_variant	19/20
NPC1L1	XM_011515326.4	c.3597C>T	p.Tyr1199=	synonymous_variant	17/18
NPC1L1	XM_011515328.3	c.2151C>T	p.Tyr717=	synonymous_variant	15/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1L1	ENST00000381160.8	c.3792C>T	p.Tyr1264=	synonymous_variant	18/19	1	NM_001101648.2	P1
NPC1L1	ENST00000289547.8	c.3873C>T	p.Tyr1291=	synonymous_variant	19/20	1
NPC1L1	ENST00000546276.5	c.3654C>T	p.Tyr1218=	synonymous_variant	17/18	1

Frequencies

GnomAD3 genomes AF: 0.158 AC: 24021 AN: 152054 Hom.: 2532 Cov.: 32

Gnomad AFR AF: 0.0516

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.0986

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.00577

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.131

GnomAD3 exomes AF: 0.166 AC: 41709 AN: 251038 Hom.: 4542 AF XY: 0.169 AC XY: 22932 AN XY: 135690

Gnomad AFR exome AF: 0.0462

Gnomad AMR exome AF: 0.0771

Gnomad ASJ exome AF: 0.217

Gnomad EAS exome AF: 0.00234

Gnomad SAS exome AF: 0.120

Gnomad FIN exome AF: 0.278

Gnomad NFE exome AF: 0.223

Gnomad OTH exome AF: 0.184

GnomAD4 exome AF: 0.206 AC: 301785 AN: 1461800 Hom.: 33850 Cov.: 36 AF XY: 0.204 AC XY: 148396 AN XY: 727194

Gnomad4 AFR exome AF: 0.0450

Gnomad4 AMR exome AF: 0.0815

Gnomad4 ASJ exome AF: 0.220

Gnomad4 EAS exome AF: 0.00413

Gnomad4 SAS exome AF: 0.126

Gnomad4 FIN exome AF: 0.275

Gnomad4 NFE exome AF: 0.227

Gnomad4 OTH exome AF: 0.193

GnomAD4 genome AF: 0.158 AC: 24016 AN: 152172 Hom.: 2531 Cov.: 32 AF XY: 0.156 AC XY: 11606 AN XY: 74374

Gnomad4 AFR AF: 0.0514

Gnomad4 AMR AF: 0.0984

Gnomad4 ASJ AF: 0.226

Gnomad4 EAS AF: 0.00578

Gnomad4 SAS AF: 0.109

Gnomad4 FIN AF: 0.284

Gnomad4 NFE AF: 0.229

Gnomad4 OTH AF: 0.128

Alfa AF: 0.197 Hom.: 4214

Bravo AF: 0.138

Asia WGS AF: 0.0570 AC: 197 AN: 3478

EpiCase AF: 0.202

EpiControl AF: 0.207

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	-0.55
Cadd	Benign	9.0
Dann	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10264715; hg19: chr7-44555406; COSMIC: COSV56931721; COSMIC: COSV56931721;