rs13306513

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000527.5(LDLR):c.940+36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0486 in 1,597,708 control chromosomes in the GnomAD database, including 2,286 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 174 hom., cov: 31)

Exomes 𝑓: 0.050 ( 2112 hom. )

Consequence

LDLR
NM_000527.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.271

Publications

7 publications found

Variant links:

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

LDLR Gene-Disease associations (from GenCC):

hypercholesterolemia, familial, 1
Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LDLR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 19-11107550-G-A is Benign according to our data. Variant chr19-11107550-G-A is described in ClinVar as Benign. ClinVar VariationId is 523739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LDLR	NM_000527.5	MANE Select	c.940+36G>A	intron	N/A	NP_000518.1	P01130-1
LDLR	NM_001195798.2		c.940+36G>A	intron	N/A	NP_001182727.1	P01130-5
LDLR	NM_001195799.2		c.817+36G>A	intron	N/A	NP_001182728.1	P01130-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LDLR	ENST00000558518.6	TSL:1 MANE Select	c.940+36G>A	intron	N/A	ENSP00000454071.1	P01130-1
LDLR	ENST00000252444.10	TSL:1	c.1198+36G>A	intron	N/A	ENSP00000252444.6	J3KMZ9
LDLR	ENST00000558013.5	TSL:1	c.940+36G>A	intron	N/A	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes

AF:

0.0391

AC:

5946

AN:

152026

Hom.:

172

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00952

Gnomad AMI

AF:

0.133

Gnomad AMR

AF:

0.0454

Gnomad ASJ

AF:

0.0681

Gnomad EAS

AF:

0.114

Gnomad SAS

AF:

0.0950

Gnomad FIN

AF:

0.0286

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0452

Gnomad OTH

AF:

0.0334

GnomAD2 exomes

AF:

0.0557

AC:

13895

AN:

249668

AF XY:

0.0576

show subpopulations

Gnomad AFR exome

AF:

0.00871

Gnomad AMR exome

AF:

0.0564

Gnomad ASJ exome

AF:

0.0683

Gnomad EAS exome

AF:

0.124

Gnomad FIN exome

AF:

0.0311

Gnomad NFE exome

AF:

0.0445

Gnomad OTH exome

AF:

0.0522

GnomAD4 exome

AF:

0.0496

AC:

71669

AN:

1445564

Hom.:

2112

Cov.:

AF XY:

0.0514

AC XY:

36978

AN XY:

719114

show subpopulations

African (AFR)

AF:

0.00749

AC:

247

AN:

32980

American (AMR)

AF:

0.0547

AC:

2417

AN:

44182

Ashkenazi Jewish (ASJ)

AF:

0.0676

AC:

1724

AN:

25510

East Asian (EAS)

AF:

0.120

AC:

4628

AN:

38634

South Asian (SAS)

AF:

0.0946

AC:

8123

AN:

85860

European-Finnish (FIN)

AF:

0.0331

AC:

1712

AN:

51744

Middle Eastern (MID)

AF:

0.0460

AC:

261

AN:

5678

European-Non Finnish (NFE)

AF:

0.0451

AC:

49672

AN:

1101690

Other (OTH)

AF:

0.0487

AC:

2885

AN:

59286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

3246

6492

9737

12983

16229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1966

3932

5898

7864

9830

<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:

0.0391

AC:

5948

AN:

152144

Hom.:

174

Cov.:

AF XY:

0.0404

AC XY:

3004

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00949

AC:

394

AN:

41528

American (AMR)

AF:

0.0453

AC:

692

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.0681

AC:

236

AN:

3468

East Asian (EAS)

AF:

0.114

AC:

587

AN:

5148

South Asian (SAS)

AF:

0.0953

AC:

459

AN:

4816

European-Finnish (FIN)

AF:

0.0286

AC:

303

AN:

10594

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0452

AC:

3075

AN:

68006

Other (OTH)

AF:

0.0331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

275

550

825

1100

1375

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<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:

0.0414

Hom.:

216

Bravo

AF:

0.0386

Asia WGS

AF:

0.0600

AC:

209

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, familial, 1 (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

5.3

(source)

DANN

Benign

0.71

PhyloP100

-0.27

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over