rs2738465

chr19-11131820-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000527.5(LDLR):c.*504G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 460,304 control chromosomes in the GnomAD database, including 20,748 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6748 hom., cov: 31)
  • Exomes 𝑓: 0.29 (14000 hom.)
• Consequence: LDLR NM_000527.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.77

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]

SPC24 (HGNC:26913): (SPC24 component of NDC80 kinetochore complex) Predicted to be involved in cell division. Located in nucleolus and nucleoplasm. Part of Ndc80 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-11131820-G-A is Benign according to our data. Variant chr19-11131820-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 328064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.*504G>A		3_prime_UTR_variant	18/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.*504G>A		3_prime_UTR_variant	18/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44402 AN: 151752 Hom.: 6735 Cov.: 31

Gnomad AFR AF: 0.283

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.491

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.280

GnomAD4 exome AF: 0.292 AC: 90098 AN: 308434 Hom.: 14000 Cov.: 0 AF XY: 0.290 AC XY: 46949 AN XY: 162030

Gnomad4 AFR exome AF: 0.268

Gnomad4 AMR exome AF: 0.286

Gnomad4 ASJ exome AF: 0.275

Gnomad4 EAS exome AF: 0.492

Gnomad4 SAS exome AF: 0.263

Gnomad4 FIN exome AF: 0.253

Gnomad4 NFE exome AF: 0.284

Gnomad4 OTH exome AF: 0.285

GnomAD4 genome AF: 0.293 AC: 44453 AN: 151870 Hom.: 6748 Cov.: 31 AF XY: 0.290 AC XY: 21528 AN XY: 74240

Gnomad4 AFR AF: 0.283

Gnomad4 AMR AF: 0.277

Gnomad4 ASJ AF: 0.277

Gnomad4 EAS AF: 0.490

Gnomad4 SAS AF: 0.286

Gnomad4 FIN AF: 0.246

Gnomad4 NFE AF: 0.296

Gnomad4 OTH AF: 0.278

Alfa AF: 0.291 Hom.: 6224

Bravo AF: 0.297

Asia WGS AF: 0.360 AC: 1250 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	-	Due to the increased occurrence of the mutation (>= 5%), this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.46
Dann	Benign	0.59

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: rs2738465; hg19: chr19-11242496;