19-11131982-T-C

Variant names:

• chr19-11131982-T-C
• rs1433099
• NM_000527.5:c.*666T>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.*666T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.67 in 187,572 control chromosomes in the GnomAD database, including 43,670 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (34364 hom., cov: 28)
  • Exomes 𝑓: 0.71 (9306 hom.)
• Consequence: LDLR NM_000527.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0310
• Publications: 66 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=-0.92).
• BP6: Variant 19-11131982-T-C is Benign according to our data. Variant chr19-11131982-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.771 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.*666T>C		3_prime_UTR	Exon 18 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.*666T>C		3_prime_UTR	Exon 18 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.*666T>C		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.*666T>C		3_prime_UTR	Exon 18 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.*666T>C		3_prime_UTR	Exon 18 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000913405.1		c.*666T>C		3_prime_UTR	Exon 18 of 18	ENSP00000583464.1

Frequencies

GnomAD3 genomes AF: 0.661 AC: 100191 AN: 151614 Hom.: 34352 Cov.: 28

Gnomad AFR AF: 0.462

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.783

Gnomad ASJ AF: 0.679

Gnomad EAS AF: 0.721

Gnomad SAS AF: 0.696

Gnomad FIN AF: 0.744

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.733

Gnomad OTH AF: 0.672

GnomAD4 exome AF: 0.710 AC: 25460 AN: 35840 Hom.: 9306 Cov.: 0 AF XY: 0.707 AC XY: 13360 AN XY: 18894

African (AFR) AF: 0.383 AC: 216 AN: 564

American (AMR) AF: 0.808 AC: 2688 AN: 3326

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 423 AN: 610

East Asian (EAS) AF: 0.717 AC: 1159 AN: 1616

South Asian (SAS) AF: 0.654 AC: 3622 AN: 5542

European-Finnish (FIN) AF: 0.706 AC: 1127 AN: 1596

Middle Eastern (MID) AF: 0.641 AC: 59 AN: 92

European-Non Finnish (NFE) AF: 0.722 AC: 14961 AN: 20708

Other (OTH) AF: 0.675 AC: 1205 AN: 1786

GnomAD4 genome AF: 0.661 AC: 100251 AN: 151732 Hom.: 34364 Cov.: 28 AF XY: 0.664 AC XY: 49202 AN XY: 74146

African (AFR) AF: 0.462 AC: 19114 AN: 41330

American (AMR) AF: 0.783 AC: 11911 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.679 AC: 2356 AN: 3470

East Asian (EAS) AF: 0.721 AC: 3704 AN: 5140

South Asian (SAS) AF: 0.696 AC: 3348 AN: 4808

European-Finnish (FIN) AF: 0.744 AC: 7842 AN: 10540

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.733 AC: 49805 AN: 67932

Other (OTH) AF: 0.669 AC: 1404 AN: 2100

Alfa AF: 0.707 Hom.: 124042

Bravo AF: 0.657

Asia WGS AF: 0.680 AC: 2363 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	-0.92
CADD	Benign	3.6
DANN	Benign	0.36
PhyloP100		0.031
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1433099; hg19: chr19-11242658; COSMIC: COSV52945335; COSMIC: COSV52945335;