rs217434

Variant names:

• chr7-44513639-A-G
• rs217434
• NM_001101648.2:c.3807T>C

Variant summary

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

The NM_013389.3(NPC1L1):​c.3888T>C​(p.Val1296Val) 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_013389.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.508
• Publications: 27 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=-0.81).
• BP6: Variant 7-44513639-A-G is Benign according to our data. Variant chr7-44513639-A-G is described in ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013389.3. 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.3807T>C	p.Val1269Val	synonymous	Exon 19 of 19	NP_001095118.1
	NPC1L1	NM_013389.3		c.3888T>C	p.Val1296Val	synonymous	Exon 20 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.3807T>C	p.Val1269Val	synonymous	Exon 19 of 19	ENSP00000370552.3
	NPC1L1	ENST00000289547.8	TSL:1	c.3888T>C	p.Val1296Val	synonymous	Exon 20 of 20	ENSP00000289547.4
	NPC1L1	ENST00000546276.5	TSL:1	c.3669T>C	p.Val1223Val	synonymous	Exon 18 of 18	ENSP00000438033.1

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

GnomAD2 exomes AF: 0.159 AC: 39467 AN: 248704 AF XY: 0.163

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 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

African (AFR) AF: 0.162 AC: 5427 AN: 33438

American (AMR) AF: 0.0825 AC: 3691 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 5011 AN: 26134

East Asian (EAS) AF: 0.00416 AC: 165 AN: 39698

South Asian (SAS) AF: 0.162 AC: 13948 AN: 86198

European-Finnish (FIN) AF: 0.194 AC: 10305 AN: 53192

Middle Eastern (MID) AF: 0.171 AC: 838 AN: 4914

European-Non Finnish (NFE) AF: 0.202 AC: 225007 AN: 1111916

Other (OTH) AF: 0.182 AC: 10950 AN: 60288

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

African (AFR) AF: 0.156 AC: 6492 AN: 41502

American (AMR) AF: 0.113 AC: 1725 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 656 AN: 3470

East Asian (EAS) AF: 0.00559 AC: 29 AN: 5188

South Asian (SAS) AF: 0.140 AC: 674 AN: 4824

European-Finnish (FIN) AF: 0.195 AC: 2071 AN: 10604

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 13999 AN: 67972

Other (OTH) AF: 0.145 AC: 306 AN: 2114

Alfa AF: 0.185 Hom.: 3918

Bravo AF: 0.162

Asia WGS AF: 0.0770 AC: 268 AN: 3478

EpiCase AF: 0.189

EpiControl AF: 0.194

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	-0.81
CADD	Benign	1.1
DANN	Benign	0.52
PhyloP100		0.51
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)		0.0		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: rs217434; hg19: chr7-44553238; COSMIC: COSV56922474; COSMIC: COSV56922474;