19-11113505-C-T

Position:

• chr19-11113505-C-T

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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 id is 251806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113505-C-T is described in Lovd as [Likely_benign]. Variant chr19-11113505-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1359-30C>T		intron_variant		ENST00000558518.6
MIR6886	NR_106946.1	n.32C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1359-30C>T		intron_variant		1	NM_000527.5	P3
MIR6886	ENST00000619864.1	n.32C>T		non_coding_transcript_exon_variant	1/1

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

GnomAD3 exomes AF: 0.398 AC: 99474 AN: 250150 Hom.: 21399 AF XY: 0.405 AC XY: 54798 AN XY: 135338

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 SAS exome AF: 0.388

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

Gnomad4 AFR exome AF: 0.0754

Gnomad4 AMR exome AF: 0.426

Gnomad4 ASJ exome AF: 0.469

Gnomad4 EAS exome AF: 0.143

Gnomad4 SAS exome AF: 0.394

Gnomad4 FIN exome AF: 0.483

Gnomad4 NFE exome AF: 0.460

Gnomad4 OTH exome AF: 0.417

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

Gnomad4 AFR AF: 0.0905

Gnomad4 AMR AF: 0.437

Gnomad4 ASJ AF: 0.456

Gnomad4 EAS AF: 0.171

Gnomad4 SAS AF: 0.391

Gnomad4 FIN AF: 0.506

Gnomad4 NFE AF: 0.451

Gnomad4 OTH AF: 0.366

Alfa AF: 0.351 Hom.: 2446

Bravo AF: 0.325

Asia WGS AF: 0.267 AC: 929 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:6

Benign, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Benign, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

-

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial hypercholesterolemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 25, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.3
DANN	Benign	0.79
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: rs1003723; hg19: chr19-11224181; COSMIC: COSV52944860; COSMIC: COSV52944860;