19-11113481-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000527.5(LDLR):​c.1358+32C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,613,508 control chromosomes in the GnomAD database, including 876 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 432 hom., cov: 29)
Exomes 𝑓: 0.011 ( 444 hom. )

Consequence

LDLR
NM_000527.5 intron

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.421
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 19-11113481-C-T is Benign according to our data. Variant chr19-11113481-C-T is described in ClinVar as [Benign]. Clinvar id is 413776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LDLRNM_000527.5 linkuse as main transcriptc.1358+32C>T intron_variant ENST00000558518.6 NP_000518.1 P01130-1A0A024R7D5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkuse as main transcriptc.1358+32C>T intron_variant 1 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

GnomAD3 genomes
AF:
0.0446
AC:
6782
AN:
152068
Hom.:
426
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.141
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0183
Gnomad ASJ
AF:
0.00490
Gnomad EAS
AF:
0.000579
Gnomad SAS
AF:
0.00414
Gnomad FIN
AF:
0.00141
Gnomad MID
AF:
0.0222
Gnomad NFE
AF:
0.00775
Gnomad OTH
AF:
0.0396
GnomAD3 exomes
AF:
0.0155
AC:
3892
AN:
250884
Hom.:
185
AF XY:
0.0129
AC XY:
1755
AN XY:
135718
show subpopulations
Gnomad AFR exome
AF:
0.142
Gnomad AMR exome
AF:
0.0101
Gnomad ASJ exome
AF:
0.00427
Gnomad EAS exome
AF:
0.00114
Gnomad SAS exome
AF:
0.00395
Gnomad FIN exome
AF:
0.00148
Gnomad NFE exome
AF:
0.00833
Gnomad OTH exome
AF:
0.0121
GnomAD4 exome
AF:
0.0109
AC:
15932
AN:
1461322
Hom.:
444
Cov.:
33
AF XY:
0.0103
AC XY:
7496
AN XY:
726972
show subpopulations
Gnomad4 AFR exome
AF:
0.149
Gnomad4 AMR exome
AF:
0.0110
Gnomad4 ASJ exome
AF:
0.00440
Gnomad4 EAS exome
AF:
0.000605
Gnomad4 SAS exome
AF:
0.00408
Gnomad4 FIN exome
AF:
0.00196
Gnomad4 NFE exome
AF:
0.00789
Gnomad4 OTH exome
AF:
0.0166
GnomAD4 genome
AF:
0.0448
AC:
6817
AN:
152186
Hom.:
432
Cov.:
29
AF XY:
0.0438
AC XY:
3259
AN XY:
74422
show subpopulations
Gnomad4 AFR
AF:
0.141
Gnomad4 AMR
AF:
0.0183
Gnomad4 ASJ
AF:
0.00490
Gnomad4 EAS
AF:
0.000581
Gnomad4 SAS
AF:
0.00373
Gnomad4 FIN
AF:
0.00141
Gnomad4 NFE
AF:
0.00775
Gnomad4 OTH
AF:
0.0392
Alfa
AF:
0.0231
Hom.:
39
Bravo
AF:
0.0502
Asia WGS
AF:
0.0140
AC:
48
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial hypercholesterolemia Benign:2
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 15, 2024- -
Hypercholesterolemia, familial, 1 Benign:1
Benign, criteria provided, single submitterresearchLaboratory of Genetics and Molecular Cardiology, University of São PauloMar 01, 2016- -
not provided Benign:1
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
CADD
Benign
1.0
DANN
Benign
0.41
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs6413505; hg19: chr19-11224157; API