19-11132089-A-G

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.*773A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 163,236 control chromosomes in the GnomAD database, including 4,438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4164 hom., cov: 31)
  • Exomes 𝑓: 0.20 (274 hom.)
• Consequence: LDLR NM_000527.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.33

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 19-11132089-A-G is Benign according to our data. Variant chr19-11132089-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 328072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.*773A>G		3_prime_UTR_variant	18/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.*773A>G		3_prime_UTR_variant	18/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34671 AN: 152036 Hom.: 4158 Cov.: 31

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.231

GnomAD4 exome AF: 0.202 AC: 2237 AN: 11082 Hom.: 274 Cov.: 0 AF XY: 0.194 AC XY: 1113 AN XY: 5734

Gnomad4 AFR exome AF: 0.100

Gnomad4 AMR exome AF: 0.228

Gnomad4 ASJ exome AF: 0.136

Gnomad4 EAS exome AF: 0.274

Gnomad4 SAS exome AF: 0.139

Gnomad4 FIN exome AF: 0.206

Gnomad4 NFE exome AF: 0.209

Gnomad4 OTH exome AF: 0.163

GnomAD4 genome AF: 0.228 AC: 34693 AN: 152154 Hom.: 4164 Cov.: 31 AF XY: 0.227 AC XY: 16849 AN XY: 74364

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.241

Gnomad4 ASJ AF: 0.209

Gnomad4 EAS AF: 0.384

Gnomad4 SAS AF: 0.193

Gnomad4 FIN AF: 0.218

Gnomad4 NFE AF: 0.251

Gnomad4 OTH AF: 0.230

Alfa AF: 0.241 Hom.: 3934

Bravo AF: 0.230

Asia WGS AF: 0.297 AC: 1030 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	Feb 08, 2019	Due to the increased occurrence of the mutation (>= 5%) and the current estimates of databases (LOVD 3), 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	0.092
Dann	Benign	0.37
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: rs2738466; hg19: chr19-11242765; COSMIC: COSV52945342; COSMIC: COSV52945342;