7-44515974-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001101648.2(NPC1L1):c.3634-9A>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,611,844 control chromosomes in the GnomAD database, including 52,495 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (5120 hom., cov: 31)
  • Exomes 𝑓: 0.25 (47375 hom.)
• Consequence: NPC1L1 NM_001101648.2 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001679
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.04

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 7-44515974-T-G is Benign according to our data. Variant chr7-44515974-T-G is described in ClinVar as [Benign]. Clinvar id is 403257.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1L1	NM_001101648.2	c.3634-9A>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000381160.8
NPC1L1	NM_013389.3	c.3715-9A>C		splice_polypyrimidine_tract_variant, intron_variant
NPC1L1	XM_011515326.4	c.3439-9A>C		splice_polypyrimidine_tract_variant, intron_variant
NPC1L1	XM_011515328.3	c.1993-9A>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1L1	ENST00000381160.8	c.3634-9A>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001101648.2	P1
NPC1L1	ENST00000289547.8	c.3715-9A>C		splice_polypyrimidine_tract_variant, intron_variant		1
NPC1L1	ENST00000546276.5	c.3496-9A>C		splice_polypyrimidine_tract_variant, intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37798 AN: 151122 Hom.: 5105 Cov.: 31

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.00584

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.214

GnomAD3 exomes AF: 0.211 AC: 52338 AN: 247858 Hom.: 6576 AF XY: 0.212 AC XY: 28429 AN XY: 134160

Gnomad AFR exome AF: 0.292

Gnomad AMR exome AF: 0.110

Gnomad ASJ exome AF: 0.253

Gnomad EAS exome AF: 0.00256

Gnomad SAS exome AF: 0.160

Gnomad FIN exome AF: 0.289

Gnomad NFE exome AF: 0.260

Gnomad OTH exome AF: 0.224

GnomAD4 exome AF: 0.248 AC: 361547 AN: 1460606 Hom.: 47375 Cov.: 38 AF XY: 0.245 AC XY: 177826 AN XY: 726524

Gnomad4 AFR exome AF: 0.301

Gnomad4 AMR exome AF: 0.117

Gnomad4 ASJ exome AF: 0.257

Gnomad4 EAS exome AF: 0.00446

Gnomad4 SAS exome AF: 0.167

Gnomad4 FIN exome AF: 0.287

Gnomad4 NFE exome AF: 0.265

Gnomad4 OTH exome AF: 0.241

GnomAD4 genome AF: 0.250 AC: 37850 AN: 151238 Hom.: 5120 Cov.: 31 AF XY: 0.247 AC XY: 18209 AN XY: 73856

Gnomad4 AFR AF: 0.294

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.266

Gnomad4 EAS AF: 0.00585

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.298

Gnomad4 NFE AF: 0.266

Gnomad4 OTH AF: 0.211

Alfa AF: 0.263 Hom.: 2369

Bravo AF: 0.239

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	-0.93
Cadd	Benign	2.2
Dann	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.13		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: rs217428; hg19: chr7-44555573; COSMIC: COSV56922725; COSMIC: COSV56922725;