rs2738457

Variant names:

• chr19-11126593-G-A
• rs2738457
• NM_000527.5:c.2312-1415G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000527.5(LDLR):​c.2312-1415G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 151,830 control chromosomes in the GnomAD database, including 4,068 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (4068 hom., cov: 30)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.258
• Publications: 6 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]

LDLR Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen, Genomics England PanelApp
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.368 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.2312-1415G>A		intron	N/A	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.2312-1415G>A		intron	N/A	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.2189-1415G>A		intron	N/A	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.2312-1415G>A		intron	N/A	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.2570-1415G>A		intron	N/A	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.2312-1415G>A		intron	N/A	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34016 AN: 151712 Hom.: 4064 Cov.: 30

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.225

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.224 AC: 34038 AN: 151830 Hom.: 4068 Cov.: 30 AF XY: 0.222 AC XY: 16499 AN XY: 74186

African (AFR) AF: 0.159 AC: 6576 AN: 41438

American (AMR) AF: 0.238 AC: 3616 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 725 AN: 3468

East Asian (EAS) AF: 0.382 AC: 1964 AN: 5136

South Asian (SAS) AF: 0.182 AC: 878 AN: 4812

European-Finnish (FIN) AF: 0.221 AC: 2327 AN: 10540

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.254 AC: 17247 AN: 67916

Other (OTH) AF: 0.224 AC: 472 AN: 2106

Alfa AF: 0.236 Hom.: 574

Bravo AF: 0.226

Asia WGS AF: 0.292 AC: 1012 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.8
DANN	Benign	0.41
PhyloP100		-0.26
Mutation Taster		=100/0	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: rs2738457; hg19: chr19-11237269;