NM_000527.5:c.*504G>A

Variant names:

• chr19-11131820-G-A
• rs2738465
• NM_000527.5:c.*504G>A

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.*504G>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 0.292 in 460,304 control chromosomes in the GnomAD database, including 20,748 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6748 hom., cov: 31)
  • Exomes 𝑓: 0.29 (14000 hom.)
• Consequence: LDLR NM_000527.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.77
• Publications: 21 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=-0.9).
• BP6: Variant 19-11131820-G-A is Benign according to our data. Variant chr19-11131820-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.474 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.*504G>A		3_prime_UTR	Exon 18 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.*504G>A		3_prime_UTR	Exon 18 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.*504G>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.*504G>A		3_prime_UTR	Exon 18 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.*504G>A		3_prime_UTR	Exon 18 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000913405.1		c.*504G>A		3_prime_UTR	Exon 18 of 18	ENSP00000583464.1

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44402 AN: 151752 Hom.: 6735 Cov.: 31

Gnomad AFR AF: 0.283

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.491

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.280

GnomAD4 exome AF: 0.292 AC: 90098 AN: 308434 Hom.: 14000 Cov.: 0 AF XY: 0.290 AC XY: 46949 AN XY: 162030

African (AFR) AF: 0.268 AC: 2552 AN: 9514

American (AMR) AF: 0.286 AC: 3185 AN: 11148

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 2698 AN: 9796

East Asian (EAS) AF: 0.492 AC: 9391 AN: 19106

South Asian (SAS) AF: 0.263 AC: 8934 AN: 33946

European-Finnish (FIN) AF: 0.253 AC: 4399 AN: 17420

Middle Eastern (MID) AF: 0.226 AC: 310 AN: 1374

European-Non Finnish (NFE) AF: 0.284 AC: 53501 AN: 188128

Other (OTH) AF: 0.285 AC: 5128 AN: 18002

GnomAD4 genome AF: 0.293 AC: 44453 AN: 151870 Hom.: 6748 Cov.: 31 AF XY: 0.290 AC XY: 21528 AN XY: 74240

African (AFR) AF: 0.283 AC: 11735 AN: 41406

American (AMR) AF: 0.277 AC: 4223 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 962 AN: 3468

East Asian (EAS) AF: 0.490 AC: 2524 AN: 5148

South Asian (SAS) AF: 0.286 AC: 1370 AN: 4792

European-Finnish (FIN) AF: 0.246 AC: 2600 AN: 10584

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.296 AC: 20086 AN: 67930

Other (OTH) AF: 0.278 AC: 587 AN: 2110

Alfa AF: 0.292 Hom.: 9694

Bravo AF: 0.297

Asia WGS AF: 0.360 AC: 1250 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.46
DANN	Benign	0.59
PhyloP100		-1.8
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: rs2738465; hg19: chr19-11242496;