rs55642005

Variant names:

• chr19-11110830-A-C
• rs55642005
• NM_000527.5:c.1060+59A>C

Your query was ambiguous. Multiple possible variants found:

• chr19-11110830-A-C
• chr19-11110830-A-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000527.5(LDLR):​c.1060+59A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00443 in 1,595,674 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (27 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.397
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-11110830-A-C is Benign according to our data. Variant chr19-11110830-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 251631.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00338 (515/152252) while in subpopulation NFE AF = 0.00526 (358/68008). AF 95% confidence interval is 0.00481. There are 4 homozygotes in GnomAd4. There are 228 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1060+59A>C		intron_variant	Intron 7 of 17	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1060+59A>C		intron_variant	Intron 7 of 17	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 514 AN: 152134 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.00664

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00526

Gnomad OTH AF: 0.00909

GnomAD4 exome AF: 0.00454 AC: 6553 AN: 1443422 Hom.: 27 AF XY: 0.00449 AC XY: 3226 AN XY: 718964

African (AFR) AF: 0.000691 AC: 23 AN: 33284

American (AMR) AF: 0.00289 AC: 129 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00469 AC: 122 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.000674 AC: 58 AN: 86000

European-Finnish (FIN) AF: 0.000612 AC: 28 AN: 45746

Middle Eastern (MID) AF: 0.00558 AC: 32 AN: 5736

European-Non Finnish (NFE) AF: 0.00539 AC: 5944 AN: 1102402

Other (OTH) AF: 0.00362 AC: 217 AN: 59952

GnomAD4 genome AF: 0.00338 AC: 515 AN: 152252 Hom.: 4 Cov.: 32 AF XY: 0.00306 AC XY: 228 AN XY: 74460

African (AFR) AF: 0.00125 AC: 52 AN: 41564

American (AMR) AF: 0.00327 AC: 50 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00664 AC: 23 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00526 AC: 358 AN: 68008

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00413 Hom.: 0

Bravo AF: 0.00348

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:1

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.6
DANN	Benign	0.45
PhyloP100		-0.40
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55642005; hg19: chr19-11221506;