rs192390193

Variant names:

• chr19-11110811-G-A
• rs192390193
• NM_000527.5:c.1060+40G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000527.5(LDLR):​c.1060+40G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00341 in 1,607,716 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 0.0026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0035 (17 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.471

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-11110811-G-A is Benign according to our data. Variant chr19-11110811-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 251630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11110811-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00259 (394/152218) while in subpopulation NFE AF= 0.00413 (281/68008). AF 95% confidence interval is 0.00373. There are 0 homozygotes in gnomad4. There are 175 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 17 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1060+40G>A		intron_variant	Intron 7 of 17	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1060+40G>A		intron_variant	Intron 7 of 17	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 394 AN: 152100 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00413

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00413

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00252 AC: 621 AN: 246888 Hom.: 0 AF XY: 0.00259 AC XY: 347 AN XY: 133984

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00433

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.00349 AC: 5083 AN: 1455498 Hom.: 17 Cov.: 33 AF XY: 0.00331 AC XY: 2398 AN XY: 724354

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00253

Gnomad4 ASJ exome AF: 0.000805

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00119

Gnomad4 NFE exome AF: 0.00421

Gnomad4 OTH exome AF: 0.00294

GnomAD4 genome AF: 0.00259 AC: 394 AN: 152218 Hom.: 0 Cov.: 31 AF XY: 0.00235 AC XY: 175 AN XY: 74432

Gnomad4 AFR AF: 0.000867

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00413

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00308 Hom.: 0

Bravo AF: 0.00282

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:4

Feb 08, 2019

Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Due to the current estimates of databases (LOVD 3), this variant is classified as likely benign. -

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

May 20, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Familial hypercholesterolemia Benign:1

Jul 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.89
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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: rs192390193; hg19: chr19-11221487;