rs12983082

chr19-11105885-A-Cchr19-11105885-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000527.5(LDLR):c.694+285A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 152,048 control chromosomes in the GnomAD database, including 11,095 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency: Genomes: 𝑓 0.34 (11095 hom., cov: 33)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.380

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-11105885-A-C is Benign according to our data. Variant chr19-11105885-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.694+285A>C		intron_variant		ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.694+285A>C		intron_variant		1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.343 AC: 52185 AN: 151930 Hom.: 11108 Cov.: 33

Gnomad AFR AF: 0.0914

Gnomad AMI AF: 0.350

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.513

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.368

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

GnomAD4 genome AF: 0.343 AC: 52162 AN: 152048 Hom.: 11095 Cov.: 33 AF XY: 0.347 AC XY: 25797 AN XY: 74322

Gnomad4 AFR AF: 0.0912

Gnomad4 AMR AF: 0.438

Gnomad4 ASJ AF: 0.454

Gnomad4 EAS AF: 0.171

Gnomad4 SAS AF: 0.393

Gnomad4 FIN AF: 0.513

Gnomad4 NFE AF: 0.452

Gnomad4 OTH AF: 0.366

Alfa AF: 0.348 Hom.: 1991

Bravo AF: 0.326

Asia WGS AF: 0.275 AC: 957 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	5.3
Dann	Benign	0.70

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: rs12983082; hg19: chr19-11216561;