rs17248748

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000527.5(LDLR):​c.68-4859C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 151,722 control chromosomes in the GnomAD database, including 15 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 0.011 ( 15 hom., cov: 32)

Consequence

LDLR
NM_000527.5 intron

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.287

Publications

5 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
  • homozygous familial hypercholesterolemia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

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=-0.81).
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0105 (1598/151722) while in subpopulation NFE AF = 0.0172 (1166/67930). AF 95% confidence interval is 0.0163. There are 15 homozygotes in GnomAd4. There are 782 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 15 AD,AR,SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LDLRNM_000527.5 linkc.68-4859C>T intron_variant Intron 1 of 17 ENST00000558518.6 NP_000518.1 P01130-1A0A024R7D5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkc.68-4859C>T intron_variant Intron 1 of 17 1 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

GnomAD3 genomes
AF:
0.0105
AC:
1598
AN:
151620
Hom.:
15
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00293
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00683
Gnomad ASJ
AF:
0.00231
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00438
Gnomad FIN
AF:
0.0152
Gnomad MID
AF:
0.00637
Gnomad NFE
AF:
0.0172
Gnomad OTH
AF:
0.00819
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
AF:
0.0105
AC:
1598
AN:
151722
Hom.:
15
Cov.:
32
AF XY:
0.0106
AC XY:
782
AN XY:
74096
show subpopulations
African (AFR)
AF:
0.00292
AC:
121
AN:
41370
American (AMR)
AF:
0.00682
AC:
104
AN:
15240
Ashkenazi Jewish (ASJ)
AF:
0.00231
AC:
8
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5162
South Asian (SAS)
AF:
0.00439
AC:
21
AN:
4788
European-Finnish (FIN)
AF:
0.0152
AC:
159
AN:
10468
Middle Eastern (MID)
AF:
0.00685
AC:
2
AN:
292
European-Non Finnish (NFE)
AF:
0.0172
AC:
1166
AN:
67930
Other (OTH)
AF:
0.00811
AC:
17
AN:
2096
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.504
Heterozygous variant carriers
0
80
159
239
318
398
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
20
40
60
80
100
<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:
0.0157
Hom.:
27
Bravo
AF:
0.00931
Asia WGS
AF:
0.00260
AC:
9
AN:
3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
CADD
Benign
6.2
DANN
Benign
0.83
PhyloP100
0.29
Mutation Taster
=100/0
polymorphism

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

Other links and lift over

dbSNP: rs17248748; hg19: chr19-11206040; API