rs12983082

Variant names:

• chr19-11105885-A-C
• rs12983082
• NM_000527.5:c.694+285A>C

Your query was ambiguous. Multiple possible variants found:

• chr19-11105885-A-C
• chr19-11105885-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 17 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• 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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.694+285A>C		intron_variant	Intron 4 of 17	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.694+285A>C		intron_variant	Intron 4 of 17	1	NM_000527.5	ENSP00000454071.1

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

African (AFR) AF: 0.0912 AC: 3784 AN: 41510

American (AMR) AF: 0.438 AC: 6679 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1574 AN: 3470

East Asian (EAS) AF: 0.171 AC: 885 AN: 5162

South Asian (SAS) AF: 0.393 AC: 1895 AN: 4824

European-Finnish (FIN) AF: 0.513 AC: 5415 AN: 10558

Middle Eastern (MID) AF: 0.435 AC: 127 AN: 292

European-Non Finnish (NFE) AF: 0.452 AC: 30712 AN: 67966

Other (OTH) AF: 0.366 AC: 774 AN: 2114

Alfa AF: 0.376 Hom.: 3914

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
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism (auto)

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: rs12983082; hg19: chr19-11216561;