rs55792959

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.941-39C>T variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BA1 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BA1: FAF=0.005249 (0.5249%) in European (Non-Finnish) exomes (gnomAD v2.1.1). So BA1 is met.BP4: The variant is not predicted to affect the splicing process by SpliceAI. So, BP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA030745/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.0041 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0056 ( 32 hom. )

Consequence

LDLR
NM_000527.5 intron

Scores

Clinical Significance

Benign reviewed by expert panel U:3B:9

Conservation

PhyloP100: -0.0280

Publications

0 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

Specifications for LDLR are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

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.941-39C>T	intron	N/A	NP_000518.1	P01130-1
LDLR	NM_001195798.2		c.941-39C>T	intron	N/A	NP_001182727.1	P01130-5
LDLR	NM_001195799.2		c.818-39C>T	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.941-39C>T	intron	N/A	ENSP00000454071.1	P01130-1
LDLR	ENST00000252444.10	TSL:1	c.1199-39C>T	intron	N/A	ENSP00000252444.6	J3KMZ9
LDLR	ENST00000558013.5	TSL:1	c.941-39C>T	intron	N/A	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes

AF:

0.00410

AC:

623

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00413

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00663

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.00364

AC:

908

AN:

249520

AF XY:

0.00384

show subpopulations

Gnomad AFR exome

AF:

0.000931

Gnomad AMR exome

AF:

0.00235

Gnomad ASJ exome

AF:

0.00489

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00318

Gnomad NFE exome

AF:

0.00561

Gnomad OTH exome

AF:

0.00410

GnomAD4 exome

AF:

0.00561

AC:

8191

AN:

1459876

Hom.:

Cov.:

AF XY:

0.00558

AC XY:

4049

AN XY:

726214

show subpopulations

African (AFR)

AF:

0.000927

AC:

AN:

33444

American (AMR)

AF:

0.00269

AC:

120

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

128

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39620

South Asian (SAS)

AF:

0.00162

AC:

140

AN:

86242

European-Finnish (FIN)

AF:

0.00300

AC:

158

AN:

52604

Middle Eastern (MID)

AF:

0.00419

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00653

AC:

7252

AN:

1111166

Other (OTH)

AF:

0.00561

AC:

338

AN:

60298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

372

743

1115

1486

1858

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

270

540

810

1080

1350

<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:

0.00409

AC:

623

AN:

152198

Hom.:

Cov.:

AF XY:

0.00376

AC XY:

280

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

41532

American (AMR)

AF:

0.00413

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00125

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00198

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00663

AC:

451

AN:

68018

Other (OTH)

AF:

0.00758

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

104

138

173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00422

Hom.:

Bravo

AF:

0.00441

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, familial, 1 (6)

Familial hypercholesterolemia (2)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

6.5

(source)

DANN

Benign

0.66

PhyloP100

-0.028

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(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

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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