Genetic Variant LDLR:c.*223G>C (chr19-11131539-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000527.5(LDLR):c.*223G>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 0.0000243 in 700,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

LDLR
NM_000527.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.17

Publications

4 publications found

Variant links:

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]

LDLR links:

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]

SPC24 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0735558).

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LDLR	NM_000527.5	MANE Select	c.*223G>C	3_prime_UTR	Exon 18 of 18	NP_000518.1	P01130-1
LDLR	NM_001195798.2		c.*223G>C	3_prime_UTR	Exon 18 of 18	NP_001182727.1	P01130-5
LDLR	NM_001195799.2		c.*223G>C	3_prime_UTR	Exon 17 of 17	NP_001182728.1	P01130-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LDLR	ENST00000558518.6	TSL:1 MANE Select	c.*223G>C	3_prime_UTR	Exon 18 of 18	ENSP00000454071.1	P01130-1
LDLR	ENST00000252444.10	TSL:1	c.*223G>C	3_prime_UTR	Exon 18 of 18	ENSP00000252444.6	J3KMZ9
LDLR	ENST00000558013.5	TSL:1	c.*223G>C	3_prime_UTR	Exon 18 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000731

AC:

AN:

136726

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000182

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000292

AC:

AN:

548502

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

296880

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15542

American (AMR)

AF:

0.00

AC:

AN:

34008

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19856

East Asian (EAS)

AF:

0.00

AC:

AN:

32068

South Asian (SAS)

AF:

0.00

AC:

AN:

62538

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4028

European-Non Finnish (NFE)

AF:

0.0000506

AC:

AN:

316002

Other (OTH)

AF:

0.00

AC:

AN:

30414

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152030

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74252

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41398

American (AMR)

AF:

0.00

AC:

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000132

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.028

(source)

DANN

Benign

0.33

DEOGEN2

Benign

0.0091

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.23

MetaRNN

Benign

0.074

PhyloP100

-2.2

MVP

0.32

GERP RS

-6.5

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over