rs41306974

chr19-11127961-G-Achr19-11127961-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000527.5(LDLR):c.2312-47G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,549,938 control chromosomes in the GnomAD database, including 165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (14 hom., cov: 31)
  • Exomes 𝑓: 0.013 (151 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.749

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-11127961-G-A is Benign according to our data. Variant chr19-11127961-G-A is described in ClinVar as [Benign]. Clinvar id is 252278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11127961-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0112 (1699/152138) while in subpopulation NFE AF= 0.0173 (1173/67986). AF 95% confidence interval is 0.0164. There are 14 homozygotes in gnomad4. There are 810 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.2312-47G>A		intron_variant		ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.2312-47G>A		intron_variant		1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1700 AN: 152020 Hom.: 14 Cov.: 31

Gnomad AFR AF: 0.00242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0132

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.00877

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0104 AC: 2612 AN: 250328 Hom.: 22 AF XY: 0.0106 AC XY: 1439 AN XY: 135368

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00853

Gnomad ASJ exome AF: 0.0114

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00431

Gnomad FIN exome AF: 0.00714

Gnomad NFE exome AF: 0.0160

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0132 AC: 18435 AN: 1397800 Hom.: 151 Cov.: 25 AF XY: 0.0131 AC XY: 9154 AN XY: 699180

Gnomad4 AFR exome AF: 0.00224

Gnomad4 AMR exome AF: 0.00921

Gnomad4 ASJ exome AF: 0.0124

Gnomad4 EAS exome AF: 0.0000508

Gnomad4 SAS exome AF: 0.00452

Gnomad4 FIN exome AF: 0.00764

Gnomad4 NFE exome AF: 0.0153

Gnomad4 OTH exome AF: 0.0110

GnomAD4 genome AF: 0.0112 AC: 1699 AN: 152138 Hom.: 14 Cov.: 31 AF XY: 0.0109 AC XY: 810 AN XY: 74362

Gnomad4 AFR AF: 0.00241

Gnomad4 AMR AF: 0.0155

Gnomad4 ASJ AF: 0.0132

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.00877

Gnomad4 NFE AF: 0.0173

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0126 Hom.: 2

Bravo AF: 0.0114

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:1

Benign, criteria provided, single submitter

literature only

LDLR-LOVD, British Heart Foundation

Mar 25, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.1
Dann	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs41306974; hg19: chr19-11238637;