rs14158

Variant names:

• chr19-11131368-G-A
• rs14158
• NM_000527.5:c.*52G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11131368-G-A
• chr19-11131368-G-C
• chr19-11131368-G-T

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.*52G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,565,802 control chromosomes in the GnomAD database, including 46,594 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4143 hom., cov: 32)
  • Exomes 𝑓: 0.24 (42451 hom.)
• Consequence: LDLR NM_000527.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.517
• Publications: 47 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]

SPC24 (HGNC:26913): (SPC24 component of NDC80 kinetochore complex) Predicted to be involved in cell division. Located in nucleolus and nucleoplasm. Part of Ndc80 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 19-11131368-G-A is Benign according to our data. Variant chr19-11131368-G-A is described in ClinVar as Benign. ClinVar VariationId is 265910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.369 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.*52G>A		3_prime_UTR	Exon 18 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.*52G>A		3_prime_UTR	Exon 18 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.*52G>A		3_prime_UTR	Exon 17 of 17	NP_001182728.1	P01130-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.*52G>A		3_prime_UTR	Exon 18 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.*52G>A		3_prime_UTR	Exon 18 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.*52G>A		3_prime_UTR	Exon 18 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34515 AN: 151948 Hom.: 4136 Cov.: 32

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.228

GnomAD2 exomes AF: 0.243 AC: 61151 AN: 251262 AF XY: 0.239

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.218

Gnomad EAS exome AF: 0.382

Gnomad FIN exome AF: 0.219

Gnomad NFE exome AF: 0.252

Gnomad OTH exome AF: 0.250

GnomAD4 exome AF: 0.241 AC: 340384 AN: 1413734 Hom.: 42451 Cov.: 25 AF XY: 0.239 AC XY: 168693 AN XY: 706344

African (AFR) AF: 0.160 AC: 5194 AN: 32444

American (AMR) AF: 0.256 AC: 11449 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 5553 AN: 25858

East Asian (EAS) AF: 0.399 AC: 15728 AN: 39426

South Asian (SAS) AF: 0.179 AC: 15246 AN: 85284

European-Finnish (FIN) AF: 0.229 AC: 12236 AN: 53396

Middle Eastern (MID) AF: 0.171 AC: 971 AN: 5678

European-Non Finnish (NFE) AF: 0.243 AC: 259960 AN: 1068194

Other (OTH) AF: 0.239 AC: 14047 AN: 58786

GnomAD4 genome AF: 0.227 AC: 34540 AN: 152068 Hom.: 4143 Cov.: 32 AF XY: 0.226 AC XY: 16762 AN XY: 74318

African (AFR) AF: 0.174 AC: 7212 AN: 41496

American (AMR) AF: 0.239 AC: 3646 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 722 AN: 3470

East Asian (EAS) AF: 0.383 AC: 1977 AN: 5162

South Asian (SAS) AF: 0.193 AC: 931 AN: 4820

European-Finnish (FIN) AF: 0.218 AC: 2302 AN: 10582

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.251 AC: 17039 AN: 67978

Other (OTH) AF: 0.227 AC: 479 AN: 2106

Alfa AF: 0.244 Hom.: 19530

Bravo AF: 0.229

Asia WGS AF: 0.296 AC: 1028 AN: 3478

EpiCase AF: 0.232

EpiControl AF: 0.236

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hypercholesterolemia, familial, 1 (4)
-	-	2	not provided (2)
-	-	1	Familial hypercholesterolemia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.0
DANN	Benign	0.57
PhyloP100		-0.52
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: rs14158; hg19: chr19-11242044; COSMIC: COSV52943415; COSMIC: COSV52943415;