19-11089332-C-T

Variant names:

• chr19-11089332-C-T
• rs17249141
• NR_163945.1:n.328G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NR_163945.1(LDLR-AS1):​n.328G>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 0.00112 in 516,738 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: LDLR-AS1 NR_163945.1 non_coding_transcript_exon
• Clinical Significance: Benign reviewed by expert panel U:1 B:8
• Conservation: PhyloP100: 0.824
• Publications: 23 publications found

Genes affected

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

ENSG00000307752 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 19-11089332-C-T is Benign according to our data. Variant chr19-11089332-C-T is described in ClinVar as Benign. ClinVar VariationId is 250927.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High Homozygotes in GnomAd4 at 3 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.328G>A		non_coding_transcript_exon	Exon 1 of 1
	LDLR	NM_000527.5	MANE Select	c.-217C>T		upstream_gene	N/A	NP_000518.1
	LDLR	NM_001195798.2		c.-217C>T		upstream_gene	N/A	NP_001182727.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.-217C>T		upstream_gene	N/A	ENSP00000454071.1
	LDLR	ENST00000558013.5	TSL:1	c.-217C>T		upstream_gene	N/A	ENSP00000453346.1
	LDLR	ENST00000557933.5	TSL:5	c.-217C>T		upstream_gene	N/A	ENSP00000453557.1

Frequencies

GnomAD3 genomes AF: 0.00309 AC: 470 AN: 152102 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00192

GnomAD4 exome AF: 0.000294 AC: 107 AN: 364518 Hom.: 0 Cov.: 3 AF XY: 0.000252 AC XY: 48 AN XY: 190622

African (AFR) AF: 0.00903 AC: 89 AN: 9856

American (AMR) AF: 0.000551 AC: 7 AN: 12694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11804

East Asian (EAS) AF: 0.00 AC: 0 AN: 26078

South Asian (SAS) AF: 0.00 AC: 0 AN: 30188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1672

European-Non Finnish (NFE) AF: 0.00000449 AC: 1 AN: 222908

Other (OTH) AF: 0.000455 AC: 10 AN: 21978

GnomAD4 genome AF: 0.00310 AC: 472 AN: 152220 Hom.: 3 Cov.: 32 AF XY: 0.00312 AC XY: 232 AN XY: 74428

African (AFR) AF: 0.0104 AC: 433 AN: 41536

American (AMR) AF: 0.00229 AC: 35 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

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: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00152 Hom.: 1

Bravo AF: 0.00338

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	Familial hypercholesterolemia (4)
-	1	3	Hypercholesterolemia, familial, 1 (4)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.3
DANN	Benign	0.84
PhyloP100		0.82
PromoterAI		0.33	Neutral

Splicing

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

Other links and lift over

dbSNP: rs17249141; hg19: chr19-11200008;