19-11131631-G-C

Position:

chr19-11131631-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000527.5(LDLR):c.*315G>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 0.838 in 624,540 control chromosomes in the GnomAD database, including 221,183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.80 ( 49823 hom., cov: 29)

Exomes 𝑓: 0.85 ( 171360 hom. )

Consequence

LDLR
NM_000527.5 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.261

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BP6

Variant 19-11131631-G-C is Benign according to our data. Variant chr19-11131631-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 328058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11131631-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.876 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.*315G>C		3_prime_UTR_variant	18/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.*315G>C		3_prime_UTR_variant	18/18	1	NM_000527.5	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.804

AC:

122048

AN:

151760

Hom.:

49799

Cov.:

show subpopulations

Gnomad AFR

AF:

0.658

Gnomad AMI

AF:

0.907

Gnomad AMR

AF:

0.817

Gnomad ASJ

AF:

0.838

Gnomad EAS

AF:

0.713

Gnomad SAS

AF:

0.796

Gnomad FIN

AF:

0.881

Gnomad MID

AF:

0.851

Gnomad NFE

AF:

0.881

Gnomad OTH

AF:

0.833

GnomAD3 exomes

AF:

0.819

AC:

59038

AN:

72086

Hom.:

24367

AF XY:

0.823

AC XY:

30761

AN XY:

37394

show subpopulations

Gnomad AFR exome

AF:

0.653

Gnomad AMR exome

AF:

0.816

Gnomad ASJ exome

AF:

0.838

Gnomad EAS exome

AF:

0.725

Gnomad SAS exome

AF:

0.779

Gnomad FIN exome

AF:

0.880

Gnomad NFE exome

AF:

0.881

Gnomad OTH exome

AF:

0.849

GnomAD4 exome

AF:

0.849

AC:

401273

AN:

472662

Hom.:

171360

Cov.:

AF XY:

0.848

AC XY:

213684

AN XY:

251960

show subpopulations

Gnomad4 AFR exome

AF:

0.659

Gnomad4 AMR exome

AF:

0.818

Gnomad4 ASJ exome

AF:

0.851

Gnomad4 EAS exome

AF:

0.696

Gnomad4 SAS exome

AF:

0.795

Gnomad4 FIN exome

AF:

0.882

Gnomad4 NFE exome

AF:

0.883

Gnomad4 OTH exome

AF:

0.848

GnomAD4 genome

AF:

0.804

AC:

122126

AN:

151878

Hom.:

49823

Cov.:

AF XY:

0.804

AC XY:

59725

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.658

Gnomad4 AMR

AF:

0.818

Gnomad4 ASJ

AF:

0.838

Gnomad4 EAS

AF:

0.712

Gnomad4 SAS

AF:

0.796

Gnomad4 FIN

AF:

0.881

Gnomad4 NFE

AF:

0.881

Gnomad4 OTH

AF:

0.831

Alfa

AF:

0.846

Hom.:

7424

Bravo

AF:

0.793

Asia WGS

AF:

0.737

AC:

2563

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	Jun 11, 2018	Due to the increased occurrence of the mutation (>= 5%) and the current estimates of databases (LOVD 3), this variant is classified as likely benign. -

Familial hypercholesterolemia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jun 30, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.53

DANN

Benign

0.39

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over