rs145293532

Variant names:

• chr19-11128142-C-T
• rs145293532
• NM_000527.5:c.2389+57C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000527.5(LDLR):​c.2389+57C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00644 in 1,516,204 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0065 (65 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0400
• Publications: 0 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-11128142-C-T is Benign according to our data. Variant chr19-11128142-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 252311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00622 (947/152228) while in subpopulation SAS AF = 0.012 (58/4820). AF 95% confidence interval is 0.00956. There are 7 homozygotes in GnomAd4. There are 551 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2389+57C>T		intron_variant	Intron 16 of 17	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2389+57C>T		intron_variant	Intron 16 of 17	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.00625 AC: 950 AN: 152110 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00662

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0155

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00709

Gnomad OTH AF: 0.00812

GnomAD4 exome AF: 0.00646 AC: 8816 AN: 1363976 Hom.: 65 AF XY: 0.00674 AC XY: 4612 AN XY: 684030

African (AFR) AF: 0.000950 AC: 30 AN: 31570

American (AMR) AF: 0.00374 AC: 167 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 478 AN: 25588

East Asian (EAS) AF: 0.0000765 AC: 3 AN: 39204

South Asian (SAS) AF: 0.0123 AC: 1035 AN: 84438

European-Finnish (FIN) AF: 0.0134 AC: 700 AN: 52400

Middle Eastern (MID) AF: 0.0218 AC: 120 AN: 5516

European-Non Finnish (NFE) AF: 0.00570 AC: 5837 AN: 1023434

Other (OTH) AF: 0.00779 AC: 446 AN: 57228

GnomAD4 genome AF: 0.00622 AC: 947 AN: 152228 Hom.: 7 Cov.: 31 AF XY: 0.00740 AC XY: 551 AN XY: 74448

African (AFR) AF: 0.00128 AC: 53 AN: 41550

American (AMR) AF: 0.00661 AC: 101 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.0120 AC: 58 AN: 4820

European-Finnish (FIN) AF: 0.0155 AC: 164 AN: 10608

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00709 AC: 482 AN: 68014

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00736 Hom.: 2

Bravo AF: 0.00449

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:2

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.4
DANN	Benign	0.61
PhyloP100		-0.040
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

Other links and lift over

dbSNP: rs145293532; hg19: chr19-11238818;