rs10423288

Variant names:

• chr19-11105170-T-C
• rs10423288
• NM_000527.5:c.314-50T>C

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.314-50T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0296 in 1,610,442 control chromosomes in the GnomAD database, including 1,929 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (484 hom., cov: 33)
  • Exomes 𝑓: 0.026 (1445 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.566
• Publications: 4 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=-0.81).
• BP6: Variant 19-11105170-T-C is Benign according to our data. Variant chr19-11105170-T-C is described in ClinVar as Benign. ClinVar VariationId is 265898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.314-50T>C		intron_variant	Intron 3 of 17	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.314-50T>C		intron_variant	Intron 3 of 17	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 9118 AN: 152066 Hom.: 478 Cov.: 33

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.0557

Gnomad FIN AF: 0.0231

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0154

Gnomad OTH AF: 0.0523

GnomAD2 exomes AF: 0.0553 AC: 13502 AN: 244044 AF XY: 0.0491

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.0301

Gnomad EAS exome AF: 0.103

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.0157

Gnomad OTH exome AF: 0.0413

GnomAD4 exome AF: 0.0264 AC: 38536 AN: 1458258 Hom.: 1445 Cov.: 33 AF XY: 0.0263 AC XY: 19086 AN XY: 725562

African (AFR) AF: 0.129 AC: 4308 AN: 33474

American (AMR) AF: 0.142 AC: 6354 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0289 AC: 755 AN: 26136

East Asian (EAS) AF: 0.123 AC: 4892 AN: 39696

South Asian (SAS) AF: 0.0523 AC: 4508 AN: 86242

European-Finnish (FIN) AF: 0.0234 AC: 1171 AN: 50048

Middle Eastern (MID) AF: 0.0229 AC: 132 AN: 5768

European-Non Finnish (NFE) AF: 0.0130 AC: 14443 AN: 1111826

Other (OTH) AF: 0.0327 AC: 1973 AN: 60352

GnomAD4 genome AF: 0.0602 AC: 9154 AN: 152184 Hom.: 484 Cov.: 33 AF XY: 0.0608 AC XY: 4528 AN XY: 74414

African (AFR) AF: 0.128 AC: 5316 AN: 41514

American (AMR) AF: 0.102 AC: 1562 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3472

East Asian (EAS) AF: 0.101 AC: 523 AN: 5166

South Asian (SAS) AF: 0.0560 AC: 270 AN: 4824

European-Finnish (FIN) AF: 0.0231 AC: 245 AN: 10616

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0154 AC: 1046 AN: 67996

Other (OTH) AF: 0.0508 AC: 107 AN: 2108

Alfa AF: 0.0363 Hom.: 442

Bravo AF: 0.0703

Asia WGS AF: 0.100 AC: 349 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:2

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

5/95 non-FH individuals -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.74
DANN	Benign	0.60
PhyloP100		-0.57
PromoterAI		-0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs10423288; hg19: chr19-11215846; COSMIC: COSV52943549; COSMIC: COSV52943549;