rs55642005

Positions:

• chr19-11110830-A-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000527.5(LDLR):​c.1060+59A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00443 in 1,595,674 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (27 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.397

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-11110830-A-C is Benign according to our data. Variant chr19-11110830-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 251631.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11110830-A-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1060+59A>C		intron_variant		ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1060+59A>C		intron_variant		1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 514 AN: 152134 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.00664

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00526

Gnomad OTH AF: 0.00909

GnomAD4 exome AF: 0.00454 AC: 6553 AN: 1443422 Hom.: 27 AF XY: 0.00449 AC XY: 3226 AN XY: 718964

Gnomad4 AFR exome AF: 0.000691

Gnomad4 AMR exome AF: 0.00289

Gnomad4 ASJ exome AF: 0.00469

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000674

Gnomad4 FIN exome AF: 0.000612

Gnomad4 NFE exome AF: 0.00539

Gnomad4 OTH exome AF: 0.00362

GnomAD4 genome AF: 0.00338 AC: 515 AN: 152252 Hom.: 4 Cov.: 32 AF XY: 0.00306 AC XY: 228 AN XY: 74460

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00664

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00526

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00413 Hom.: 0

Bravo AF: 0.00348

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:1

Likely 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	-0.83
CADD	Benign	1.6
DANN	Benign	0.45

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: rs55642005; hg19: chr19-11221506;