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GeneBe

rs688

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000527.5(LDLR):c.1773C>T(p.Asn591=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 151818 control chromosomes in the gnomAD Genomes database, including 10439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. NG591N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.34 ( 10439 hom., cov: 31)
Exomes 𝑓: 0.39 ( 20537 hom. )

Consequence

LDLR
NM_000527.5 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: -4.22

Links

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.74).
BP6
?
Variant 19-11116926-C-T is Benign according to our data. Variant chr19-11116926-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 200917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11116926-C-T is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-4.22 with no splicing effect.
BA1
?
GnomAd highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LDLRNM_000527.5 linkuse as main transcriptc.1773C>T p.Asn591= synonymous_variant 12/18 ENST00000558518.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LDLRENST00000558518.6 linkuse as main transcriptc.1773C>T p.Asn591= synonymous_variant 12/181 NM_000527.5 P3P01130-1

Frequencies

GnomAD3 genomes
AF:
0.337
AC:
51230
AN:
151818
Hom.:
10439
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.107
Gnomad AMI
AF:
0.349
Gnomad AMR
AF:
0.427
Gnomad ASJ
AF:
0.419
Gnomad EAS
AF:
0.173
Gnomad SAS
AF:
0.393
Gnomad FIN
AF:
0.493
Gnomad MID
AF:
0.434
Gnomad NFE
AF:
0.437
Gnomad OTH
AF:
0.362
GnomAD3 exomes
AF:
0.389
AC:
97866
AN:
251472
Hom.:
20537
AF XY:
0.396
AC XY:
53812
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.100
Gnomad AMR exome
AF:
0.415
Gnomad ASJ exome
AF:
0.432
Gnomad EAS exome
AF:
0.179
Gnomad SAS exome
AF:
0.389
Gnomad FIN exome
AF:
0.483
Gnomad NFE exome
AF:
0.434
Gnomad OTH exome
AF:
0.409
GnomAD4 exome
AF:
0.426
AC:
622001
AN:
1461646
Hom.:
136666
AF XY:
0.425
AC XY:
309181
AN XY:
727136
show subpopulations
Gnomad4 AFR exome
AF:
0.0953
Gnomad4 AMR exome
AF:
0.419
Gnomad4 ASJ exome
AF:
0.435
Gnomad4 EAS exome
AF:
0.148
Gnomad4 SAS exome
AF:
0.393
Gnomad4 FIN exome
AF:
0.472
Gnomad4 NFE exome
AF:
0.447
Gnomad4 OTH exome
AF:
0.407
Alfa
AF:
0.414
Hom.:
25163
Bravo
AF:
0.321
Asia WGS
AF:
0.266
AC:
923
AN:
3478
EpiCase
AF:
0.438
EpiControl
AF:
0.442

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:19
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:9
Likely benign, criteria provided, single submitterclinical testingDepartment of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und KollegenJun 11, 2018Due to the increased occurrence of the mutation (>= 5%) and the current estimates of databases (LOVD 3), this variant is classified as likely benign. -
Benign, criteria provided, single submitterresearchCardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo JorgeMar 01, 201619 Hmz + 62 htz / 125 non-FH individuals; MAF = 48,3% in 86 Spanish healthy individuals -
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJun 22, 2017- -
Benign, criteria provided, single submitterliterature onlyLDLR-LOVD, British Heart FoundationMar 25, 2016- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This 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. -
Benign, no assertion criteria providedresearchLaboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum-- -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJun 10, 2021- -
Benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 25, 2022- -
Benign, criteria provided, single submitterclinical testingMolecular Genetics, Royal Melbourne HospitalNov 20, 2020Population allele frequency is 38% (rs688, 106341/277102 alleles in gnomAD v2.0.2). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as Benign. Following criteria met: BA1. -
not specified Benign:5
Benign, criteria provided, single submitterclinical testingPreventionGenetics, Part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 31, 2015p.Asn591Asn in exon 12 of LDLR: This variant is not expected to have clinical si gnificance because it has been identified in 37.8% (45902/121396) of chromosomes tested by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs688). -
Familial hypercholesterolemia Benign:3
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Benign, no assertion criteria providedclinical testingCohesion PhenomicsFeb 09, 2023- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 28, 2022- -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 08, 2015This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.74
Cadd
Benign
0.096
Dann
Benign
0.70
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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.

Other links and lift over

dbSNP: rs688; hg19: chr19-11227602; COSMIC: COSV52942945; COSMIC: COSV52942945; API