rs145293532

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 252311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11128142-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 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

Gnomad4 AFR exome AF: 0.000950

Gnomad4 AMR exome AF: 0.00374

Gnomad4 ASJ exome AF: 0.0187

Gnomad4 EAS exome AF: 0.0000765

Gnomad4 SAS exome AF: 0.0123

Gnomad4 FIN exome AF: 0.0134

Gnomad4 NFE exome AF: 0.00570

Gnomad4 OTH exome AF: 0.00779

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

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00661

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.0155

Gnomad4 NFE AF: 0.00709

Gnomad4 OTH AF: 0.00803

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

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

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

Other links and lift over

dbSNP: rs145293532; hg19: chr19-11238818;