rs6511721

chr19-11095899-G-Achr19-11095899-G-Cchr19-11095899-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000527.5(LDLR):c.68-4324G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 152,066 control chromosomes in the GnomAD database, including 32,678 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 0.63 (32678 hom., cov: 32)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.68-4324G>A		intron_variant		ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.68-4324G>A		intron_variant		1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.630 AC: 95789 AN: 151948 Hom.: 32612 Cov.: 32

Gnomad AFR AF: 0.907

Gnomad AMI AF: 0.647

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.494

Gnomad EAS AF: 0.747

Gnomad SAS AF: 0.526

Gnomad FIN AF: 0.507

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.604

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.631 AC: 95914 AN: 152066 Hom.: 32678 Cov.: 32 AF XY: 0.626 AC XY: 46535 AN XY: 74306

Gnomad4 AFR AF: 0.907

Gnomad4 AMR AF: 0.490

Gnomad4 ASJ AF: 0.494

Gnomad4 EAS AF: 0.747

Gnomad4 SAS AF: 0.525

Gnomad4 FIN AF: 0.507

Gnomad4 NFE AF: 0.519

Gnomad4 OTH AF: 0.607

Alfa AF: 0.527 Hom.: 4875

Bravo AF: 0.646

Asia WGS AF: 0.655 AC: 2280 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.39
Dann	Benign	0.85
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

Other links and lift over

dbSNP: rs6511721; hg19: chr19-11206575;