rs6413503

Positions:

• chr19-11131228-G-A
• chr19-11131228-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. Variant has been reported in Lovd as Likely benign (no stars).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-11131228-G-A is Benign according to our data. Variant chr19-11131228-G-A is described in Lovd as [Likely_benign].
• 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.2548-53G>A		intron_variant		ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.2548-53G>A		intron_variant		1	NM_000527.5	P3

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

Gnomad4 AFR exome AF: 0.143

Gnomad4 AMR exome AF: 0.0105

Gnomad4 ASJ exome AF: 0.00319

Gnomad4 EAS exome AF: 0.0175

Gnomad4 SAS exome AF: 0.0114

Gnomad4 FIN exome AF: 0.0157

Gnomad4 NFE exome AF: 0.0132

Gnomad4 OTH exome AF: 0.0191

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

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.0235

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.0123

Gnomad4 NFE AF: 0.0128

Gnomad4 OTH AF: 0.0430

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs6413503; hg19: chr19-11241904; COSMIC: COSV52943559; COSMIC: COSV52943559;