19-11132746-C-T

Variant names:

• chr19-11132746-C-T
• rs7254521
• NM_000527.5:c.*1430C>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.*1430C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 151,308 control chromosomes in the GnomAD database, including 1,350 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene LDLR is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.13 (1350 hom., cov: 30)
  • Exomes 𝑓: 0.063 (0 hom.)
• Consequence: LDLR NM_000527.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.45
• Publications: 8 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

Specifications for LDLR are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-11132746-C-T is Benign according to our data. Variant chr19-11132746-C-T is described in ClinVar as Benign. ClinVar VariationId is 328101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.14 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.*1430C>T		3_prime_UTR	Exon 18 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.*1430C>T		3_prime_UTR	Exon 18 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.*1430C>T		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.*1430C>T		3_prime_UTR	Exon 18 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.*1430C>T		3_prime_UTR	Exon 18 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000913405.1		c.*1430C>T		3_prime_UTR	Exon 18 of 18	ENSP00000583464.1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19560 AN: 151150 Hom.: 1348 Cov.: 30

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.0944

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.00738

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.146

GnomAD4 exome AF: 0.0625 AC: 3 AN: 48 Hom.: 0 Cov.: 0 AF XY: 0.0714 AC XY: 3 AN XY: 42

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0789 AC: 3 AN: 38

Other (OTH) AF: 0.00 AC: 0 AN: 6

GnomAD4 genome AF: 0.129 AC: 19573 AN: 151260 Hom.: 1350 Cov.: 30 AF XY: 0.128 AC XY: 9455 AN XY: 73842

African (AFR) AF: 0.143 AC: 5902 AN: 41266

American (AMR) AF: 0.0943 AC: 1431 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 541 AN: 3470

East Asian (EAS) AF: 0.00758 AC: 39 AN: 5142

South Asian (SAS) AF: 0.124 AC: 595 AN: 4800

European-Finnish (FIN) AF: 0.122 AC: 1254 AN: 10290

Middle Eastern (MID) AF: 0.161 AC: 47 AN: 292

European-Non Finnish (NFE) AF: 0.136 AC: 9204 AN: 67818

Other (OTH) AF: 0.148 AC: 310 AN: 2096

Alfa AF: 0.0587 Hom.: 56

Bravo AF: 0.127

Asia WGS AF: 0.100 AC: 348 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.1
DANN	Benign	0.54
PhyloP100		-1.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7254521; hg19: chr19-11243422;