Genetic Variant NM_001101648.2:c.-133A>G (chr7-44541392-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001101648.2(NPC1L1):c.-133A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 759,692 control chromosomes in the GnomAD database, including 31,190 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.22 ( 4712 hom., cov: 33)

Exomes 𝑓: 0.28 ( 26478 hom. )

Consequence

NPC1L1
NM_001101648.2 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.434

Publications

30 publications found

Variant links:

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]

NPC1L1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.312 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1L1	NM_001101648.2 link	c.-133A>G		upstream_gene_variant		ENST00000381160.8	NP_001095118.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein
NPC1L1	ENST00000381160.8 link	c.-133A>G	upstream_gene_variant	1	NM_001101648.2	ENSP00000370552.3
NPC1L1	ENST00000289547.8 link	c.-133A>G	upstream_gene_variant	1		ENSP00000289547.4
NPC1L1	ENST00000546276.5 link	c.-133A>G	upstream_gene_variant	1		ENSP00000438033.1
NPC1L1	ENST00000423141.1 link	c.-133A>G	upstream_gene_variant	1		ENSP00000404670.1

Frequencies

GnomAD3 genomes

AF:

0.219

AC:

33315

AN:

152094

Hom.:

4712

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0644

Gnomad AMI

AF:

0.432

Gnomad AMR

AF:

0.241

Gnomad ASJ

AF:

0.270

Gnomad EAS

AF:

0.00964

Gnomad SAS

AF:

0.226

Gnomad FIN

AF:

0.226

Gnomad MID

AF:

0.263

Gnomad NFE

AF:

0.316

Gnomad OTH

AF:

0.259

GnomAD4 exome

AF:

0.280

AC:

170341

AN:

607480

Hom.:

26478

AF XY:

0.280

AC XY:

87414

AN XY:

312004

show subpopulations

African (AFR)

AF:

0.0593

AC:

957

AN:

16148

American (AMR)

AF:

0.230

AC:

5018

AN:

21820

Ashkenazi Jewish (ASJ)

AF:

0.279

AC:

4151

AN:

14900

East Asian (EAS)

AF:

0.0121

AC:

383

AN:

31584

South Asian (SAS)

AF:

0.249

AC:

12283

AN:

49428

European-Finnish (FIN)

AF:

0.235

AC:

7418

AN:

31510

Middle Eastern (MID)

AF:

0.295

AC:

1150

AN:

3896

European-Non Finnish (NFE)

AF:

0.321

AC:

130715

AN:

406738

Other (OTH)

AF:

0.263

AC:

8266

AN:

31456

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

5747

11494

17240

22987

28734

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2328

4656

6984

9312

11640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.219

AC:

33313

AN:

152212

Hom.:

4712

Cov.:

AF XY:

0.213

AC XY:

15870

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.0643

AC:

2673

AN:

41550

American (AMR)

AF:

0.241

AC:

3688

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.270

AC:

936

AN:

3472

East Asian (EAS)

AF:

0.00947

AC:

AN:

5176

South Asian (SAS)

AF:

0.226

AC:

1092

AN:

4832

European-Finnish (FIN)

AF:

0.226

AC:

2395

AN:

10596

Middle Eastern (MID)

AF:

0.255

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.316

AC:

21471

AN:

67978

Other (OTH)

AF:

0.256

AC:

541

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1277

2554

3831

5108

6385

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

354

708

1062

1416

1770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.278

Hom.:

20817

Bravo

AF:

0.213

Asia WGS

AF:

0.122

AC:

426

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.71

PhyloP100

-0.43

PromoterAI

0.075

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over