dbSNP rs17249057: LDLR:c.*1510T>C (chr19-11132826-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000527.5(LDLR):c.*1510T>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 0.227 in 151,798 control chromosomes in the GnomAD database, including 4,129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4128 hom., cov: 31)

Exomes 𝑓: 0.27 ( 1 hom. )

Consequence

LDLR
NM_000527.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.505

Publications

7 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:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 19-11132826-T-C is Benign according to our data. Variant chr19-11132826-T-C is described in ClinVar as Benign. ClinVar VariationId is 328103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.367 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LDLR	NM_000527.5	MANE Select	c.*1510T>C	3_prime_UTR	Exon 18 of 18	NP_000518.1	P01130-1
LDLR	NM_001195798.2		c.*1510T>C	3_prime_UTR	Exon 18 of 18	NP_001182727.1	P01130-5
LDLR	NM_001195799.2		c.*1510T>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.*1510T>C	3_prime_UTR	Exon 18 of 18	ENSP00000454071.1	P01130-1
LDLR	ENST00000252444.10	TSL:1	c.*1510T>C	3_prime_UTR	Exon 18 of 18	ENSP00000252444.6	J3KMZ9
LDLR	ENST00000913405.1		c.*1510T>C	3_prime_UTR	Exon 18 of 18	ENSP00000583464.1

Frequencies

GnomAD3 genomes

AF:

0.227

AC:

34478

AN:

151634

Hom.:

4122

Cov.:

show subpopulations

Gnomad AFR

AF:

0.175

Gnomad AMI

AF:

0.188

Gnomad AMR

AF:

0.238

Gnomad ASJ

AF:

0.209

Gnomad EAS

AF:

0.383

Gnomad SAS

AF:

0.192

Gnomad FIN

AF:

0.216

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.251

Gnomad OTH

AF:

0.230

GnomAD4 exome

AF:

0.271

AC:

AN:

Hom.:

Cov.:

AF XY:

0.275

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AF:

1.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.250

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

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:

0.227

AC:

34500

AN:

151750

Hom.:

4128

Cov.:

AF XY:

0.226

AC XY:

16728

AN XY:

74132

show subpopulations

African (AFR)

AF:

0.175

AC:

7256

AN:

41426

American (AMR)

AF:

0.239

AC:

3632

AN:

15206

Ashkenazi Jewish (ASJ)

AF:

0.209

AC:

723

AN:

3466

East Asian (EAS)

AF:

0.381

AC:

1957

AN:

5130

South Asian (SAS)

AF:

0.192

AC:

926

AN:

4814

European-Finnish (FIN)

AF:

0.216

AC:

2268

AN:

10506

Middle Eastern (MID)

AF:

0.218

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.251

AC:

17022

AN:

67898

Other (OTH)

AF:

0.229

AC:

482

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

1164

2329

3493

4658

5822

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

372

744

1116

1488

1860

<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:

0.239

Hom.:

576

Bravo

AF:

0.230

Asia WGS

AF:

0.296

AC:

1027

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, familial, 1 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

3.2

(source)

DANN

Benign

0.43

PhyloP100

0.51

Splicing

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over