rs3826810

Variant names:

• chr19-11131457-G-A
• rs3826810
• NM_000527.5:c.*141G>A

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.*141G>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 0.0567 in 900,160 control chromosomes in the GnomAD database, including 1,804 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (410 hom., cov: 32)
  • Exomes 𝑓: 0.055 (1394 hom.)
• Consequence: LDLR NM_000527.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.22
• Publications: 20 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 (MetaRNN=0.0017805696).
• BP6: Variant 19-11131457-G-A is Benign according to our data. Variant chr19-11131457-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.*141G>A		3_prime_UTR	Exon 18 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.*141G>A		3_prime_UTR	Exon 18 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.*141G>A		3_prime_UTR	Exon 17 of 17	NP_001182728.1	P01130-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.*141G>A		3_prime_UTR	Exon 18 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.*141G>A		3_prime_UTR	Exon 18 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.*141G>A		3_prime_UTR	Exon 18 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.0648 AC: 9855 AN: 152052 Hom.: 402 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.0383

Gnomad ASJ AF: 0.0683

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.0921

Gnomad FIN AF: 0.0278

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0447

Gnomad OTH AF: 0.0522

GnomAD2 exomes AF: 0.0632 AC: 11782 AN: 186552 AF XY: 0.0642

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.0523

Gnomad ASJ exome AF: 0.0683

Gnomad EAS exome AF: 0.120

Gnomad FIN exome AF: 0.0314

Gnomad NFE exome AF: 0.0463

Gnomad OTH exome AF: 0.0521

GnomAD4 exome AF: 0.0551 AC: 41193 AN: 747990 Hom.: 1394 Cov.: 10 AF XY: 0.0570 AC XY: 22581 AN XY: 396092

African (AFR) AF: 0.110 AC: 2096 AN: 19140

American (AMR) AF: 0.0495 AC: 1825 AN: 36900

Ashkenazi Jewish (ASJ) AF: 0.0685 AC: 1462 AN: 21334

East Asian (EAS) AF: 0.112 AC: 3822 AN: 34232

South Asian (SAS) AF: 0.0933 AC: 6487 AN: 69546

European-Finnish (FIN) AF: 0.0313 AC: 1530 AN: 48928

Middle Eastern (MID) AF: 0.0488 AC: 215 AN: 4410

European-Non Finnish (NFE) AF: 0.0456 AC: 21749 AN: 476588

Other (OTH) AF: 0.0544 AC: 2007 AN: 36912

GnomAD4 genome AF: 0.0650 AC: 9884 AN: 152170 Hom.: 410 Cov.: 32 AF XY: 0.0636 AC XY: 4732 AN XY: 74408

African (AFR) AF: 0.108 AC: 4494 AN: 41504

American (AMR) AF: 0.0382 AC: 583 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0683 AC: 237 AN: 3472

East Asian (EAS) AF: 0.105 AC: 545 AN: 5166

South Asian (SAS) AF: 0.0920 AC: 444 AN: 4826

European-Finnish (FIN) AF: 0.0278 AC: 295 AN: 10608

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0448 AC: 3044 AN: 68016

Other (OTH) AF: 0.0511 AC: 108 AN: 2112

Alfa AF: 0.0551 Hom.: 491

Bravo AF: 0.0677

TwinsUK AF: 0.0456 AC: 169

ALSPAC AF: 0.0433 AC: 167

ExAC AF: 0.0533 AC: 6233

Asia WGS AF: 0.0620 AC: 218 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hypercholesterolemia, familial, 1 (2)
-	-	2	not provided (2)
-	-	1	Familial hypercholesterolemia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	11
DANN	Benign	0.47
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0018	T
PhyloP100		2.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.32	N
Sift	Pathogenic	0.0	D
Vest4		0.099
GERP RS		-2.4
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3826810; hg19: chr19-11242133; COSMIC: COSV52942248; COSMIC: COSV52942248;