rs10264715

Variant names:

• chr7-44515807-G-A
• rs10264715
• NM_001101648.2:c.3792C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001101648.2(NPC1L1):​c.3792C>T​(p.Tyr1264Tyr) 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
• Publications: 20 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001101648.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1L1	NM_001101648.2	MANE Select	c.3792C>T	p.Tyr1264Tyr	synonymous	Exon 18 of 19	NP_001095118.1
	NPC1L1	NM_013389.3		c.3873C>T	p.Tyr1291Tyr	synonymous	Exon 19 of 20	NP_037521.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1L1	ENST00000381160.8	TSL:1 MANE Select	c.3792C>T	p.Tyr1264Tyr	synonymous	Exon 18 of 19	ENSP00000370552.3
	NPC1L1	ENST00000289547.8	TSL:1	c.3873C>T	p.Tyr1291Tyr	synonymous	Exon 19 of 20	ENSP00000289547.4
	NPC1L1	ENST00000546276.5	TSL:1	c.3654C>T	p.Tyr1218Tyr	synonymous	Exon 17 of 18	ENSP00000438033.1

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

GnomAD2 exomes AF: 0.166 AC: 41709 AN: 251038 AF XY: 0.169

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 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

African (AFR) AF: 0.0450 AC: 1506 AN: 33480

American (AMR) AF: 0.0815 AC: 3646 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 5750 AN: 26134

East Asian (EAS) AF: 0.00413 AC: 164 AN: 39700

South Asian (SAS) AF: 0.126 AC: 10831 AN: 86254

European-Finnish (FIN) AF: 0.275 AC: 14673 AN: 53410

Middle Eastern (MID) AF: 0.139 AC: 802 AN: 5768

European-Non Finnish (NFE) AF: 0.227 AC: 252771 AN: 1111940

Other (OTH) AF: 0.193 AC: 11642 AN: 60392

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

African (AFR) AF: 0.0514 AC: 2137 AN: 41546

American (AMR) AF: 0.0984 AC: 1503 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 785 AN: 3466

East Asian (EAS) AF: 0.00578 AC: 30 AN: 5188

South Asian (SAS) AF: 0.109 AC: 525 AN: 4826

European-Finnish (FIN) AF: 0.284 AC: 3007 AN: 10572

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.229 AC: 15598 AN: 67980

Other (OTH) AF: 0.128 AC: 271 AN: 2112

Alfa AF: 0.184 Hom.: 5044

Bravo AF: 0.138

Asia WGS AF: 0.0570 AC: 197 AN: 3478

EpiCase AF: 0.202

EpiControl AF: 0.207

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.0
DANN	Benign	0.78
PhyloP100		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10264715; hg19: chr7-44555406; COSMIC: COSV56931721; COSMIC: COSV56931721;