19-11131228-G-A

Variant names:

• chr19-11131228-G-A
• rs6413503
• NM_000527.5:c.2548-53G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000527.5(LDLR):​c.2548-53G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,595,554 control chromosomes in the GnomAD database, including 928 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.049 (433 hom., cov: 32)
  • Exomes 𝑓: 0.016 (495 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.25
• Publications: 5 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]

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• 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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2548-53G>A		intron_variant	Intron 17 of 17	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2548-53G>A		intron_variant	Intron 17 of 17	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.0486 AC: 7398 AN: 152142 Hom.: 430 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0187

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0235

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.0123

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.0435

GnomAD4 exome AF: 0.0163 AC: 23492 AN: 1443294 Hom.: 495 AF XY: 0.0157 AC XY: 11299 AN XY: 719134

African (AFR) AF: 0.143 AC: 4731 AN: 33100

American (AMR) AF: 0.0105 AC: 471 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00319 AC: 83 AN: 26022

East Asian (EAS) AF: 0.0175 AC: 693 AN: 39582

South Asian (SAS) AF: 0.0114 AC: 981 AN: 85874

European-Finnish (FIN) AF: 0.0157 AC: 836 AN: 53380

Middle Eastern (MID) AF: 0.0155 AC: 89 AN: 5730

European-Non Finnish (NFE) AF: 0.0132 AC: 14466 AN: 1095100

Other (OTH) AF: 0.0191 AC: 1142 AN: 59806

GnomAD4 genome AF: 0.0487 AC: 7417 AN: 152260 Hom.: 433 Cov.: 32 AF XY: 0.0489 AC XY: 3641 AN XY: 74448

African (AFR) AF: 0.141 AC: 5839 AN: 41526

American (AMR) AF: 0.0186 AC: 285 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.0235 AC: 122 AN: 5184

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4820

European-Finnish (FIN) AF: 0.0123 AC: 131 AN: 10616

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0128 AC: 872 AN: 68038

Other (OTH) AF: 0.0430 AC: 91 AN: 2116

Alfa AF: 0.0336 Hom.: 37

Bravo AF: 0.0533

Asia WGS AF: 0.0170 AC: 59 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0060
DANN	Benign	0.57
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6413503; hg19: chr19-11241904; COSMIC: COSV52943559; COSMIC: COSV52943559;