chr19-11113459-G-A

Variant names:

• chr19-11113459-G-A
• rs373060981
• NM_000527.5:c.1358+10G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000527.5(LDLR):​c.1358+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.67
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-11113459-G-A is Benign according to our data. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526. Variant chr19-11113459-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 431526.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1358+10G>A		intron_variant	Intron 9 of 17	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1358+10G>A		intron_variant	Intron 9 of 17	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152098 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000399 AC: 10 AN: 250904 AF XY: 0.0000295

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461536 Hom.: 0 Cov.: 33 AF XY: 0.0000165 AC XY: 12 AN XY: 727084

African (AFR) AF: 0.000179 AC: 6 AN: 33478

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.000132 AC: 7 AN: 53124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111964

Other (OTH) AF: 0.0000331 AC: 2 AN: 60392

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152098 Hom.: 0 Cov.: 29 AF XY: 0.000108 AC XY: 8 AN XY: 74294

African (AFR) AF: 0.0000966 AC: 4 AN: 41424

American (AMR) AF: 0.000197 AC: 3 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000680

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:1

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

not specified Benign:1

Dec 12, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hypercholesterolemia Benign:1

Jun 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.15
DANN	Benign	0.64
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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: rs373060981; hg19: chr19-11224135;