rs6413505

chr19-11113481-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.1358+32C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,613,508 control chromosomes in the GnomAD database, including 876 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (432 hom., cov: 29)
  • Exomes 𝑓: 0.011 (444 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.421

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=-0.82).
• BP6: Variant 19-11113481-C-T is Benign according to our data. Variant chr19-11113481-C-T is described in ClinVar as [Benign]. Clinvar id is 413776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1358+32C>T		intron_variant		ENST00000558518.6
MIR6886	NR_106946.1	n.8C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1358+32C>T		intron_variant		1	NM_000527.5	P3
MIR6886	ENST00000619864.1	n.8C>T		mature_miRNA_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0446 AC: 6782 AN: 152068 Hom.: 426 Cov.: 29

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00775

Gnomad OTH AF: 0.0396

GnomAD3 exomes AF: 0.0155 AC: 3892 AN: 250884 Hom.: 185 AF XY: 0.0129 AC XY: 1755 AN XY: 135718

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00114

Gnomad SAS exome AF: 0.00395

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00833

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0109 AC: 15932 AN: 1461322 Hom.: 444 Cov.: 33 AF XY: 0.0103 AC XY: 7496 AN XY: 726972

Gnomad4 AFR exome AF: 0.149

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.00440

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.00408

Gnomad4 FIN exome AF: 0.00196

Gnomad4 NFE exome AF: 0.00789

Gnomad4 OTH exome AF: 0.0166

GnomAD4 genome AF: 0.0448 AC: 6817 AN: 152186 Hom.: 432 Cov.: 29 AF XY: 0.0438 AC XY: 3259 AN XY: 74422

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.0183

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00775

Gnomad4 OTH AF: 0.0392

Alfa AF: 0.0231 Hom.: 39

Bravo AF: 0.0502

Asia WGS AF: 0.0140 AC: 48 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypercholesterolemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Hypercholesterolemia, familial, 1 Benign:1

Benign, criteria provided, single submitter

research

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Mar 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	1.0
Dann	Benign	0.41
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: rs6413505; hg19: chr19-11224157;