chr19-11132119-C-T

Variant names:

• chr19-11132119-C-T
• rs17242677
• NM_000527.5:c.*803C>T

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.*803C>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 0.0116 in 161,326 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (15 hom., cov: 31)
  • Exomes 𝑓: 0.0077 (2 hom.)
• Consequence: LDLR NM_000527.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.77
• Publications: 4 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 19-11132119-C-T is Benign according to our data. Variant chr19-11132119-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 684566.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 = 0.0118 (1799/152322) while in subpopulation AFR AF = 0.0156 (648/41562). AF 95% confidence interval is 0.0146. There are 15 homozygotes in GnomAd4. There are 884 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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.*803C>T		3_prime_UTR	Exon 18 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.*803C>T		3_prime_UTR	Exon 18 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.*803C>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.*803C>T		3_prime_UTR	Exon 18 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.*803C>T		3_prime_UTR	Exon 18 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000913405.1		c.*803C>T		3_prime_UTR	Exon 18 of 18	ENSP00000583464.1

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1795 AN: 152206 Hom.: 15 Cov.: 31

Gnomad AFR AF: 0.0156

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.00850

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.00766 AC: 69 AN: 9004 Hom.: 2 Cov.: 0 AF XY: 0.00663 AC XY: 31 AN XY: 4678

African (AFR) AF: 0.0263 AC: 1 AN: 38

American (AMR) AF: 0.00161 AC: 3 AN: 1864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 66

East Asian (EAS) AF: 0.00 AC: 0 AN: 162

South Asian (SAS) AF: 0.00731 AC: 7 AN: 958

European-Finnish (FIN) AF: 0.00377 AC: 2 AN: 530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 10

European-Non Finnish (NFE) AF: 0.0102 AC: 51 AN: 5018

Other (OTH) AF: 0.0140 AC: 5 AN: 358

GnomAD4 genome AF: 0.0118 AC: 1799 AN: 152322 Hom.: 15 Cov.: 31 AF XY: 0.0119 AC XY: 884 AN XY: 74472

African (AFR) AF: 0.0156 AC: 648 AN: 41562

American (AMR) AF: 0.00628 AC: 96 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5190

South Asian (SAS) AF: 0.00851 AC: 41 AN: 4818

European-Finnish (FIN) AF: 0.0124 AC: 132 AN: 10624

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0123 AC: 838 AN: 68036

Other (OTH) AF: 0.0128 AC: 27 AN: 2116

Alfa AF: 0.0123 Hom.: 2

Bravo AF: 0.0112

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.21
DANN	Benign	0.45
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs17242677; hg19: chr19-11242795;