rs5742911

Variant names:

• chr19-11132769-A-G
• rs5742911
• NM_000527.5:c.*1453A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-11132769-A-G
• chr19-11132769-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000527.5(LDLR):​c.*1453A>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 0.27 in 150,596 control chromosomes in the GnomAD database, including 5,759 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5759 hom., cov: 30)
  • Exomes 𝑓: 0.22 (0 hom.)
• Consequence: LDLR NM_000527.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.52
• Publications: 26 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-11132769-A-G is Benign according to our data. Variant chr19-11132769-A-G is described in ClinVar as Benign. ClinVar VariationId is 328102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.*1453A>G		3_prime_UTR_variant	Exon 18 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.*1453A>G		3_prime_UTR_variant	Exon 18 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.270 AC: 40590 AN: 150442 Hom.: 5753 Cov.: 30

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.277

GnomAD4 exome AF: 0.222 AC: 12 AN: 54 Hom.: 0 Cov.: 0 AF XY: 0.237 AC XY: 9 AN XY: 38

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.250 AC: 1 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.229 AC: 11 AN: 48

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.270 AC: 40607 AN: 150542 Hom.: 5759 Cov.: 30 AF XY: 0.267 AC XY: 19609 AN XY: 73352

African (AFR) AF: 0.188 AC: 7742 AN: 41100

American (AMR) AF: 0.292 AC: 4387 AN: 15022

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 797 AN: 3458

East Asian (EAS) AF: 0.377 AC: 1901 AN: 5048

South Asian (SAS) AF: 0.212 AC: 1014 AN: 4788

European-Finnish (FIN) AF: 0.277 AC: 2808 AN: 10128

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.312 AC: 21107 AN: 67706

Other (OTH) AF: 0.275 AC: 575 AN: 2088

Alfa AF: 0.244 Hom.: 1581

Bravo AF: 0.275

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.1
DANN	Benign	0.32
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5742911; hg19: chr19-11243445;