rs45591834

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_007078.3(LDB3):c.147G>A(p.Val49Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00401 in 1,614,180 control chromosomes in the GnomAD database, including 23 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. V49V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0031 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0041 ( 23 hom. )

Consequence

LDB3
NM_007078.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 2.27

Publications

4 publications found

Variant links:

Genes affected

LDB3 (HGNC:15710): (LIM domain binding 3) This gene encodes a PDZ domain-containing protein. PDZ motifs are modular protein-protein interaction domains consisting of 80-120 amino acid residues. PDZ domain-containing proteins interact with each other in cytoskeletal assembly or with other proteins involved in targeting and clustering of membrane proteins. The protein encoded by this gene interacts with alpha-actinin-2 through its N-terminal PDZ domain and with protein kinase C via its C-terminal LIM domains. The LIM domain is a cysteine-rich motif defined by 50-60 amino acids containing two zinc-binding modules. This protein also interacts with all three members of the myozenin family. Mutations in this gene have been associated with myofibrillar myopathy and dilated cardiomyopathy. Alternatively spliced transcript variants encoding different isoforms have been identified; all isoforms have N-terminal PDZ domains while only longer isoforms (1, 2 and 5) have C-terminal LIM domains. [provided by RefSeq, Jan 2010]

LDB3 Gene-Disease associations (from GenCC):

myofibrillar myopathy 4
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
familial dilated cardiomyopathy
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

LDB3 links:

ENSG00000289258 (HGNC:):

ENSG00000289258 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 10-86679420-G-A is Benign according to our data. Variant chr10-86679420-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.27 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00306 (466/152326) while in subpopulation NFE AF = 0.00475 (323/68028). AF 95% confidence interval is 0.00432. There are 0 homozygotes in GnomAd4. There are 214 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 23 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_007078.3 link	c.147G>A	p.Val49Val	synonymous_variant	Exon 3 of 14	ENST00000361373.9	NP_009009.1	O75112-1
LDB3	NM_001368067.1 link	c.147G>A	p.Val49Val	synonymous_variant	Exon 3 of 9	ENST00000263066.11	NP_001354996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LDB3	ENST00000361373.9 link	c.147G>A	p.Val49Val	synonymous_variant	Exon 3 of 14	1	NM_007078.3	ENSP00000355296.3	O75112-1
LDB3	ENST00000263066.11 link	c.147G>A	p.Val49Val	synonymous_variant	Exon 3 of 9	1	NM_001368067.1	ENSP00000263066.7	O75112-6
ENSG00000289258	ENST00000443292.2 link	c.1656G>A	p.Val552Val	synonymous_variant	Exon 13 of 18	1		ENSP00000393132.2	C9JWU6

Frequencies

GnomAD3 genomes

AF:

0.00306

AC:

466

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00475

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00298

AC:

750

AN:

251426

AF XY:

0.00307

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.00330

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00277

Gnomad NFE exome

AF:

0.00409

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00411

AC:

6002

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00403

AC XY:

2929

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.000986

AC:

AN:

33480

American (AMR)

AF:

0.00378

AC:

169

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000918

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00234

AC:

202

AN:

86258

European-Finnish (FIN)

AF:

0.00253

AC:

135

AN:

53386

Middle Eastern (MID)

AF:

0.00225

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00470

AC:

5226

AN:

1112006

Other (OTH)

AF:

0.00329

AC:

199

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

362

724

1086

1448

1810

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

204

408

612

816

1020

<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:

0.00306

AC:

466

AN:

152326

Hom.:

Cov.:

AF XY:

0.00287

AC XY:

214

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41574

American (AMR)

AF:

0.00333

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.00187

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00198

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00475

AC:

323

AN:

68028

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.00409

Hom.:

Bravo

AF:

0.00299

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00393

EpiControl

AF:

0.00439

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 19, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Val49Val in Exon 02 of LDB3: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue, is not located within t he splice consensus sequence and has been identified in 0.4% (27/7020) of Europe an American chromosomes from a broad population by the NHLBI Exome Sequencing Pr oject (http://evs.gs.washington.edu/EVS; dbSNP rs45591834). -

Mar 11, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LDB3 c.147G>A alters a conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.003 in 251426 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 119 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDB3 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.147G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with another likely pathogenic variant has been reported (TTN c.43732C>T, p.Gln14578Ter) in our internal database, providing supporting evidence for a benign role. Four ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 17, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 14, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:6

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LDB3: BP4, BS2 -

Cardiomyopathy

Benign:1

Oct 16, 2015

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Myofibrillar myopathy 4

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

LDB3-related disorder

Benign:1

Nov 14, 2022

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Dec 03, 2015

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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

-0.54

CADD

Benign

(source)

DANN

Benign

0.78

PhyloP100

2.3

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over