19-11113505-C-T

Variant names:

• chr19-11113505-C-T
• rs1003723
• NM_000527.5:c.1359-30C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000527.5(LDLR):​c.1359-30C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 1,612,554 control chromosomes in the GnomAD database, including 155,431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (11031 hom., cov: 30)
  • Exomes 𝑓: 0.44 (144400 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.637
• Publications: 41 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]

MIR6886 (HGNC:50121): (microRNA 6886) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-11113505-C-T is Benign according to our data. Variant chr19-11113505-C-T is described in ClinVar as Benign. ClinVar VariationId is 251806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1359-30C>T		intron	N/A	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1359-30C>T		intron	N/A	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1236-30C>T		intron	N/A	NP_001182728.1	P01130-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1359-30C>T		intron	N/A	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1617-30C>T		intron	N/A	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1359-30C>T		intron	N/A	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51991 AN: 151818 Hom.: 11044 Cov.: 30

Gnomad AFR AF: 0.0908

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.171

Gnomad SAS AF: 0.392

Gnomad FIN AF: 0.506

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.368

GnomAD2 exomes AF: 0.398 AC: 99474 AN: 250150 AF XY: 0.405

Gnomad AFR exome AF: 0.0825

Gnomad AMR exome AF: 0.422

Gnomad ASJ exome AF: 0.467

Gnomad EAS exome AF: 0.173

Gnomad FIN exome AF: 0.494

Gnomad NFE exome AF: 0.449

Gnomad OTH exome AF: 0.420

GnomAD4 exome AF: 0.437 AC: 638051 AN: 1460618 Hom.: 144400 Cov.: 37 AF XY: 0.436 AC XY: 317033 AN XY: 726604

African (AFR) AF: 0.0754 AC: 2524 AN: 33454

American (AMR) AF: 0.426 AC: 19018 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 12249 AN: 26130

East Asian (EAS) AF: 0.143 AC: 5682 AN: 39692

South Asian (SAS) AF: 0.394 AC: 33937 AN: 86228

European-Finnish (FIN) AF: 0.483 AC: 25608 AN: 53048

Middle Eastern (MID) AF: 0.449 AC: 2589 AN: 5762

European-Non Finnish (NFE) AF: 0.460 AC: 511265 AN: 1111266

Other (OTH) AF: 0.417 AC: 25179 AN: 60370

GnomAD4 genome AF: 0.342 AC: 51967 AN: 151936 Hom.: 11031 Cov.: 30 AF XY: 0.346 AC XY: 25688 AN XY: 74250

African (AFR) AF: 0.0905 AC: 3755 AN: 41480

American (AMR) AF: 0.437 AC: 6661 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 1582 AN: 3468

East Asian (EAS) AF: 0.171 AC: 879 AN: 5146

South Asian (SAS) AF: 0.391 AC: 1887 AN: 4824

European-Finnish (FIN) AF: 0.506 AC: 5339 AN: 10546

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.451 AC: 30646 AN: 67926

Other (OTH) AF: 0.366 AC: 773 AN: 2110

Alfa AF: 0.351 Hom.: 2446

Bravo AF: 0.325

Asia WGS AF: 0.267 AC: 929 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Hypercholesterolemia, familial, 1 (6)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Familial hypercholesterolemia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.3
DANN	Benign	0.79
PhyloP100		-0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1003723; hg19: chr19-11224181; COSMIC: COSV52944860; COSMIC: COSV52944860;