19-11131239-A-G

Variant names:

• chr19-11131239-A-G
• rs6413504
• NM_000527.5:c.2548-42A>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.2548-42A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 1,609,990 control chromosomes in the GnomAD database, including 179,445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13268 hom., cov: 32)
  • Exomes 𝑓: 0.47 (166177 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.486
• Publications: 40 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=-0.88).
• BP6: Variant 19-11131239-A-G is Benign according to our data. Variant chr19-11131239-A-G is described in ClinVar as Benign. ClinVar VariationId is 252355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.477 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.2548-42A>G		intron	N/A	NP_000518.1
	LDLR	NM_001195798.2		c.2548-48A>G		intron	N/A	NP_001182727.1
	LDLR	NM_001195799.2		c.2425-42A>G		intron	N/A	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.2548-42A>G		intron	N/A	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2806-42A>G		intron	N/A	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.2548-48A>G		intron	N/A	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60356 AN: 151928 Hom.: 13273 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.441

Gnomad AMR AF: 0.465

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.468

Gnomad FIN AF: 0.525

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.418

GnomAD2 exomes AF: 0.448 AC: 112489 AN: 251028 AF XY: 0.455

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.469

Gnomad ASJ exome AF: 0.485

Gnomad EAS exome AF: 0.315

Gnomad FIN exome AF: 0.522

Gnomad NFE exome AF: 0.478

Gnomad OTH exome AF: 0.456

GnomAD4 exome AF: 0.473 AC: 689913 AN: 1457944 Hom.: 166177 Cov.: 34 AF XY: 0.474 AC XY: 343966 AN XY: 725604

African (AFR) AF: 0.185 AC: 6175 AN: 33374

American (AMR) AF: 0.470 AC: 21017 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 12719 AN: 26116

East Asian (EAS) AF: 0.280 AC: 11104 AN: 39676

South Asian (SAS) AF: 0.468 AC: 40294 AN: 86184

European-Finnish (FIN) AF: 0.509 AC: 27179 AN: 53412

Middle Eastern (MID) AF: 0.500 AC: 2876 AN: 5748

European-Non Finnish (NFE) AF: 0.488 AC: 540940 AN: 1108468

Other (OTH) AF: 0.458 AC: 27609 AN: 60244

GnomAD4 genome AF: 0.397 AC: 60370 AN: 152046 Hom.: 13268 Cov.: 32 AF XY: 0.400 AC XY: 29739 AN XY: 74300

African (AFR) AF: 0.197 AC: 8182 AN: 41504

American (AMR) AF: 0.464 AC: 7075 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 1630 AN: 3470

East Asian (EAS) AF: 0.296 AC: 1524 AN: 5152

South Asian (SAS) AF: 0.467 AC: 2257 AN: 4828

European-Finnish (FIN) AF: 0.525 AC: 5550 AN: 10564

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.482 AC: 32741 AN: 67966

Other (OTH) AF: 0.415 AC: 877 AN: 2112

Alfa AF: 0.453 Hom.: 67185

Bravo AF: 0.382

Asia WGS AF: 0.321 AC: 1117 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hypercholesterolemia, familial, 1 (3)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.27
DANN	Benign	0.64
PhyloP100		-0.49
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: rs6413504; hg19: chr19-11241915; COSMIC: COSV52942246; COSMIC: COSV52942246;