19-11127872-A-G

Variant names:

• chr19-11127872-A-G
• rs2569538
• NM_000527.5:c.2312-136A>G

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.2312-136A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.891 in 786,086 control chromosomes in the GnomAD database, including 312,535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (57719 hom., cov: 29)
  • Exomes 𝑓: 0.90 (254816 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.38
• Publications: 15 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-11127872-A-G is Benign according to our data. Variant chr19-11127872-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 252277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.901 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.2312-136A>G		intron	N/A	NP_000518.1
	LDLR	NM_001195798.2		c.2312-136A>G		intron	N/A	NP_001182727.1
	LDLR	NM_001195799.2		c.2189-136A>G		intron	N/A	NP_001182728.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.2312-136A>G		intron	N/A	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2570-136A>G		intron	N/A	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.2312-136A>G		intron	N/A	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.870 AC: 132155 AN: 151856 Hom.: 57689 Cov.: 29

Gnomad AFR AF: 0.793

Gnomad AMI AF: 0.952

Gnomad AMR AF: 0.860

Gnomad ASJ AF: 0.878

Gnomad EAS AF: 0.916

Gnomad SAS AF: 0.874

Gnomad FIN AF: 0.910

Gnomad MID AF: 0.921

Gnomad NFE AF: 0.907

Gnomad OTH AF: 0.893

GnomAD4 exome AF: 0.896 AC: 568117 AN: 634110 Hom.: 254816 AF XY: 0.895 AC XY: 308180 AN XY: 344188

African (AFR) AF: 0.796 AC: 14127 AN: 17752

American (AMR) AF: 0.854 AC: 35138 AN: 41160

Ashkenazi Jewish (ASJ) AF: 0.884 AC: 18250 AN: 20638

East Asian (EAS) AF: 0.912 AC: 32674 AN: 35830

South Asian (SAS) AF: 0.862 AC: 59511 AN: 69034

European-Finnish (FIN) AF: 0.913 AC: 36587 AN: 40066

Middle Eastern (MID) AF: 0.880 AC: 3676 AN: 4176

European-Non Finnish (NFE) AF: 0.909 AC: 338292 AN: 372040

Other (OTH) AF: 0.894 AC: 29862 AN: 33414

GnomAD4 genome AF: 0.870 AC: 132241 AN: 151976 Hom.: 57719 Cov.: 29 AF XY: 0.872 AC XY: 64745 AN XY: 74250

African (AFR) AF: 0.793 AC: 32862 AN: 41462

American (AMR) AF: 0.860 AC: 13100 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.878 AC: 3049 AN: 3472

East Asian (EAS) AF: 0.916 AC: 4689 AN: 5120

South Asian (SAS) AF: 0.874 AC: 4193 AN: 4800

European-Finnish (FIN) AF: 0.910 AC: 9633 AN: 10586

Middle Eastern (MID) AF: 0.912 AC: 268 AN: 294

European-Non Finnish (NFE) AF: 0.907 AC: 61691 AN: 67984

Other (OTH) AF: 0.893 AC: 1888 AN: 2114

Alfa AF: 0.897 Hom.: 102094

Bravo AF: 0.863

Asia WGS AF: 0.862 AC: 2998 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.1
DANN	Benign	0.14
PhyloP100		-1.4
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: rs2569538; hg19: chr19-11238548;