rs45591834

Positions:

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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

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 links:

ENSG00000289258 (HGNC:):

ENSG00000289258 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=-0.54).

BP6

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

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 466 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDB3	NM_007078.3 linkuse as main transcript	c.147G>A	p.Val49Val	synonymous_variant	3/14	ENST00000361373.9	NP_009009.1	O75112-1
LDB3	NM_001368067.1 linkuse as main transcript	c.147G>A	p.Val49Val	synonymous_variant	3/9	ENST00000263066.11	NP_001354996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LDB3	ENST00000361373.9 linkuse as main transcript	c.147G>A	p.Val49Val	synonymous_variant	3/14	1	NM_007078.3	ENSP00000355296.3	O75112-1
LDB3	ENST00000263066.11 linkuse as main transcript	c.147G>A	p.Val49Val	synonymous_variant	3/9	1	NM_001368067.1	ENSP00000263066.7	O75112-6
ENSG00000289258	ENST00000443292.2 linkuse as main transcript	c.1656G>A	p.Val552Val	synonymous_variant	13/18	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

GnomAD3 exomes

AF:

0.00298

AC:

750

AN:

251426

Hom.:

AF XY:

0.00307

AC XY:

417

AN XY:

135902

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 SAS exome

AF:

0.00232

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

Gnomad4 AFR exome

AF:

0.000986

Gnomad4 AMR exome

AF:

0.00378

Gnomad4 ASJ exome

AF:

0.000918

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00234

Gnomad4 FIN exome

AF:

0.00253

Gnomad4 NFE exome

AF:

0.00470

Gnomad4 OTH exome

AF:

0.00329

GnomAD4 genome

AF:

0.00306

AC:

466

AN:

152326

Hom.:

Cov.:

AF XY:

0.00287

AC XY:

214

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.00333

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.00475

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00402

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 19, 2012	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). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 17, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 11, 2021	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. -

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	LDB3: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 28, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Oct 16, 2015

- -

Myofibrillar myopathy 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

LDB3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 14, 2022

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2015

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

DANN

Benign

0.78

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

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