rs8102912

Variant names:

• chr19-11095299-G-A
• rs8102912
• NM_000527.5:c.68-4924G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11095299-G-A
• chr19-11095299-G-C

Variant summary

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

The NM_000527.5(LDLR):​c.68-4924G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 151,918 control chromosomes in the GnomAD database, including 13,346 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 0.37 (13346 hom., cov: 31)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.123
• Publications: 10 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.67 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.68-4924G>A		intron	N/A	NP_000518.1
	LDLR	NM_001195798.2		c.68-4924G>A		intron	N/A	NP_001182727.1
	LDLR	NM_001195799.2		c.68-4924G>A		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.68-4924G>A		intron	N/A	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.325+4380G>A		intron	N/A	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.68-4924G>A		intron	N/A	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55817 AN: 151798 Hom.: 13300 Cov.: 31

Gnomad AFR AF: 0.676

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.530

Gnomad SAS AF: 0.256

Gnomad FIN AF: 0.303

Gnomad MID AF: 0.245

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.319

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

GnomAD4 genome AF: 0.368 AC: 55905 AN: 151918 Hom.: 13346 Cov.: 31 AF XY: 0.371 AC XY: 27530 AN XY: 74252

African (AFR) AF: 0.676 AC: 28002 AN: 41414

American (AMR) AF: 0.278 AC: 4240 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 692 AN: 3470

East Asian (EAS) AF: 0.529 AC: 2739 AN: 5176

South Asian (SAS) AF: 0.254 AC: 1227 AN: 4822

European-Finnish (FIN) AF: 0.303 AC: 3191 AN: 10526

Middle Eastern (MID) AF: 0.243 AC: 71 AN: 292

European-Non Finnish (NFE) AF: 0.220 AC: 14927 AN: 67954

Other (OTH) AF: 0.316 AC: 669 AN: 2116

Alfa AF: 0.352 Hom.: 7494

Bravo AF: 0.384

Asia WGS AF: 0.436 AC: 1518 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.2
DANN	Benign	0.55
PhyloP100		0.12
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: rs8102912; hg19: chr19-11205975;