dbSNP rs17243011: LDLR:c.*223G>A (chr19-11131539-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000527.5(LDLR):c.*223G>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 0.00298 in 700,648 control chromosomes in the GnomAD database, including 6 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 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 6 hom. )

Consequence

LDLR
NM_000527.5 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042452216).

BP6

Variant 19-11131539-G-A is Benign according to our data. Variant chr19-11131539-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 889308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00321 (1762/548500) while in subpopulation MID AF = 0.00943 (38/4028). AF 95% confidence interval is 0.00707. There are 6 homozygotes in GnomAdExome4. There are 1002 alleles in the male GnomAdExome4 subpopulation. Median coverage is 3. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LDLR	NM_000527.5	MANE Select	c.*223G>A	3_prime_UTR	Exon 18 of 18	NP_000518.1	P01130-1
LDLR	NM_001195798.2		c.*223G>A	3_prime_UTR	Exon 18 of 18	NP_001182727.1	P01130-5
LDLR	NM_001195799.2		c.*223G>A	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>A	3_prime_UTR	Exon 18 of 18	ENSP00000454071.1	P01130-1
LDLR	ENST00000252444.10	TSL:1	c.*223G>A	3_prime_UTR	Exon 18 of 18	ENSP00000252444.6	J3KMZ9
LDLR	ENST00000558013.5	TSL:1	c.*223G>A	3_prime_UTR	Exon 18 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes

AF:

0.00216

AC:

328

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000701

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00282

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00338

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00331

AC:

452

AN:

136726

AF XY:

0.00345

show subpopulations

Gnomad AFR exome

AF:

0.000449

Gnomad AMR exome

AF:

0.00405

Gnomad ASJ exome

AF:

0.00186

Gnomad EAS exome

AF:

0.0000921

Gnomad FIN exome

AF:

0.000716

Gnomad NFE exome

AF:

0.00365

Gnomad OTH exome

AF:

0.0103

GnomAD4 exome

AF:

0.00321

AC:

1762

AN:

548500

Hom.:

Cov.:

AF XY:

0.00338

AC XY:

1002

AN XY:

296878

show subpopulations

African (AFR)

AF:

0.000643

AC:

AN:

15542

American (AMR)

AF:

0.00412

AC:

140

AN:

34008

Ashkenazi Jewish (ASJ)

AF:

0.00156

AC:

AN:

19856

East Asian (EAS)

AF:

0.00

AC:

AN:

32068

South Asian (SAS)

AF:

0.00387

AC:

242

AN:

62538

European-Finnish (FIN)

AF:

0.000646

AC:

AN:

34046

Middle Eastern (MID)

AF:

0.00943

AC:

AN:

4028

European-Non Finnish (NFE)

AF:

0.00372

AC:

1174

AN:

316000

Other (OTH)

AF:

0.00345

AC:

105

AN:

30414

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

106

212

318

424

530

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00214

AC:

326

AN:

152148

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

160

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.000698

AC:

AN:

41520

American (AMR)

AF:

0.00282

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00353

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00338

AC:

230

AN:

67986

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.00216

Hom.:

Bravo

AF:

0.00206

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00182

AC:

ExAC

AF:

0.00176

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hypercholesterolemia, familial, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.014

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.0090

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.30

MetaRNN

Benign

0.0042

PhyloP100

-2.2

MVP

0.21

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over