19-11089281-G-T

Variant names:

• chr19-11089281-G-T
• rs17249134
• ENST00000828660.1:n.17C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NR_163945.1(LDLR-AS1):​n.379C>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 422,340 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (4 hom.)
• Consequence: LDLR-AS1 NR_163945.1 non_coding_transcript_exon
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.129
• Publications: 6 publications found

Genes affected

ENSG00000307752 (HGNC:):

LDLR-AS1 (HGNC:54407): (LDLR antisense RNA 1) This gene represents a regulatory lncRNA that overlaps the 5' UTR and coding sequence of the LDLR (low density lipoprotein receptor) gene. This lncRNA overlaps LDLR in the antisense orientation, and has been shown to downregulate production of the low density lipoprotein receptor. [provided by RefSeq, Jul 2019]

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 19-11089281-G-T is Benign according to our data. Variant chr19-11089281-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 250925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00658 (1002/152260) while in subpopulation AFR AF = 0.0228 (945/41534). AF 95% confidence interval is 0.0215. There are 12 homozygotes in GnomAd4. There are 478 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NR_163945.1. 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-AS1	NR_163945.1		n.379C>A		non_coding_transcript_exon	Exon 1 of 1
	LDLR	NM_000527.5	MANE Select	c.-268G>T		upstream_gene	N/A	NP_000518.1
	LDLR	NM_001195798.2		c.-268G>T		upstream_gene	N/A	NP_001182727.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000307752	ENST00000828660.1		n.17C>A		non_coding_transcript_exon	Exon 1 of 1
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.-268G>T		upstream_gene	N/A	ENSP00000454071.1
	LDLR	ENST00000558013.5	TSL:1	c.-268G>T		upstream_gene	N/A	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.00660 AC: 1004 AN: 152142 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00622

GnomAD4 exome AF: 0.000996 AC: 269 AN: 270080 Hom.: 4 AF XY: 0.000855 AC XY: 119 AN XY: 139204

African (AFR) AF: 0.0246 AC: 186 AN: 7570

American (AMR) AF: 0.00102 AC: 9 AN: 8852

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9472

East Asian (EAS) AF: 0.00 AC: 0 AN: 22404

South Asian (SAS) AF: 0.00 AC: 0 AN: 12602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22142

Middle Eastern (MID) AF: 0.000776 AC: 1 AN: 1288

European-Non Finnish (NFE) AF: 0.000190 AC: 32 AN: 168478

Other (OTH) AF: 0.00237 AC: 41 AN: 17272

GnomAD4 genome AF: 0.00658 AC: 1002 AN: 152260 Hom.: 12 Cov.: 32 AF XY: 0.00642 AC XY: 478 AN XY: 74460

African (AFR) AF: 0.0228 AC: 945 AN: 41534

American (AMR) AF: 0.00209 AC: 32 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68026

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00496 Hom.: 3

Bravo AF: 0.00773

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	2.4
DANN	Benign	0.66
PhyloP100		-0.13
PromoterAI		0.057	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17249134; hg19: chr19-11199957;