NM_000527.5:c.*517C>A

Variant names:

• chr19-11131833-C-A
• rs115882455
• NM_000527.5:c.*517C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000527.5(LDLR):​c.*517C>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 0.000894 in 433,124 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: LDLR NM_000527.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0560
• 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]

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=-0.82).
• BP6: Variant 19-11131833-C-A is Benign according to our data. Variant chr19-11131833-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 889991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00209 (319/152270) while in subpopulation AFR AF = 0.00753 (313/41562). AF 95% confidence interval is 0.00684. There are 2 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR,SD gene

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.*517C>A		3_prime_UTR	Exon 18 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.*517C>A		3_prime_UTR	Exon 18 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.*517C>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.*517C>A		3_prime_UTR	Exon 18 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.*517C>A		3_prime_UTR	Exon 18 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000913405.1		c.*517C>A		3_prime_UTR	Exon 18 of 18	ENSP00000583464.1

Frequencies

GnomAD3 genomes AF: 0.00207 AC: 315 AN: 152152 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00746

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000242 AC: 68 AN: 280854 Hom.: 0 Cov.: 0 AF XY: 0.000264 AC XY: 39 AN XY: 147544

African (AFR) AF: 0.00700 AC: 61 AN: 8714

American (AMR) AF: 0.000306 AC: 3 AN: 9798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8942

East Asian (EAS) AF: 0.00 AC: 0 AN: 17008

South Asian (SAS) AF: 0.00 AC: 0 AN: 31404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1258

European-Non Finnish (NFE) AF: 0.00000582 AC: 1 AN: 171966

Other (OTH) AF: 0.000184 AC: 3 AN: 16288

GnomAD4 genome AF: 0.00209 AC: 319 AN: 152270 Hom.: 2 Cov.: 31 AF XY: 0.00199 AC XY: 148 AN XY: 74448

African (AFR) AF: 0.00753 AC: 313 AN: 41562

American (AMR) AF: 0.000196 AC: 3 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00139 Hom.: 0

Bravo AF: 0.00227

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Familial hypercholesterolemia (1)
-	-	1	Hypercholesterolemia, familial, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.3
DANN	Benign	0.74
PhyloP100		0.056
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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: rs115882455; hg19: chr19-11242509;