ENST00000913405.1:c.-97G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP4PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.4(LDLR):c.-97G>A is a LDLR-AS1 Non Coding Transcript Variant and is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follow:PM2_Met : absent from controls in GnomAD (gnomAD v2.1.1).PP4_Met : 1 index case with Dutch lipid clinic network >=6PS4_supporting: variant met PM2 and was found in 1 index case with Dutch lipid clinic network >=6 (sequenced by progenica) from M.Arca Lab and 1 patient from Lille University & CHRU Lille (ClinVar entry) with Dutch Lipid Clinic Scoring of Probable FH LINK:https://erepo.genome.network/evrepo/ui/classification/CA305287338/MONDO:0007750/013

Frequency

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

Exomes 𝑓: 0.0000038 ( 0 hom. )

Consequence

LDLR
ENST00000913405.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:3B:2

Conservation

PhyloP100: 0.140

Publications

0 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:

LDLR-AS1 (HGNC:54407): (LDLR antisense RNA 1) This gene represents a regulatory lncRNA that overlaps the 5' UTR and coding sequence of the LDLR (low density lipoprotein receptor) gene. This lncRNA overlaps LDLR in the antisense orientation, and has been shown to downregulate production of the low density lipoprotein receptor. [provided by RefSeq, Jul 2019]

LDLR-AS1 links:

ENSG00000307752 (HGNC:):

ENSG00000307752 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000913405.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LDLR-AS1	NR_163945.1		n.208C>T	non_coding_transcript_exon	Exon 1 of 1
LDLR	NM_000527.5	MANE Select	c.-97G>A	upstream_gene	N/A	NP_000518.1	P01130-1
LDLR	NM_001195798.2		c.-97G>A	upstream_gene	N/A	NP_001182727.1	P01130-5

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
LDLR	ENST00000913405.1	c.-97G>A	5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	ENSP00000583464.1
LDLR	ENST00000856646.1	c.-97G>A	5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	ENSP00000526705.1
LDLR	ENST00000913412.1	c.-97G>A	5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	ENSP00000583471.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152176

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

GnomAD4 exome

AF:

0.00000376

AC:

AN:

798012

Hom.:

Cov.:

AF XY:

0.00000241

AC XY:

AN XY:

414428

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20622

American (AMR)

AF:

0.00

AC:

AN:

37228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20036

East Asian (EAS)

AF:

0.00

AC:

AN:

35454

South Asian (SAS)

AF:

0.0000146

AC:

AN:

68474

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44090

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2804

European-Non Finnish (NFE)

AF:

0.00000376

AC:

AN:

531444

Other (OTH)

AF:

0.00

AC:

AN:

37860

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68052

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:

0.0000283

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, familial, 1 (3)

Familial hypercholesterolemia (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

6.0

(source)

DANN

Benign

0.89

PhyloP100

0.14

PromoterAI

-0.78

Under-expression

(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