19-11132119-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000527.5(LDLR):c.*803C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 161,326 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (15 hom., cov: 31)
  • Exomes 𝑓: 0.0077 (2 hom.)
• Consequence: LDLR NM_000527.5 3_prime_UTR
• Clinical Significance: 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-11132119-C-T is Benign according to our data. Variant chr19-11132119-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 684566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 15 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.*803C>T		3_prime_UTR_variant	18/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.*803C>T		3_prime_UTR_variant	18/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1795 AN: 152206 Hom.: 15 Cov.: 31

Gnomad AFR AF: 0.0156

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.00850

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.00766 AC: 69 AN: 9004 Hom.: 2 Cov.: 0 AF XY: 0.00663 AC XY: 31 AN XY: 4678

Gnomad4 AFR exome AF: 0.0263

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00731

Gnomad4 FIN exome AF: 0.00377

Gnomad4 NFE exome AF: 0.0102

Gnomad4 OTH exome AF: 0.0140

GnomAD4 genome AF: 0.0118 AC: 1799 AN: 152322 Hom.: 15 Cov.: 31 AF XY: 0.0119 AC XY: 884 AN XY: 74472

Gnomad4 AFR AF: 0.0156

Gnomad4 AMR AF: 0.00628

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000963

Gnomad4 SAS AF: 0.00851

Gnomad4 FIN AF: 0.0124

Gnomad4 NFE AF: 0.0123

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0120 Hom.: 2

Bravo AF: 0.0112

ClinVar

Significance: 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	Illumina Laboratory Services, Illumina	Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	Feb 11, 2019	This variant is classified as benign due to location and elevation with multiple in silico prediction programs. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.21
Dann	Benign	0.45
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: rs17242677; hg19: chr19-11242795;