rs121908338

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001368067.1(LDB3):c.349G>A(p.Asp117Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00376 in 1,613,780 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0071 ( 8 hom., cov: 33)

Exomes 𝑓: 0.0034 ( 31 hom. )

Consequence

LDB3
NM_001368067.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:18

Conservation

PhyloP100: 6.87

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018208385).

BP6

Variant 10-86687073-G-A is Benign according to our data. Variant chr10-86687073-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 4733.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=11, Uncertain_significance=1}. Variant chr10-86687073-G-A is described in Lovd as [Benign]. Variant chr10-86687073-G-A is described in Lovd as [Likely_benign]. Variant chr10-86687073-G-A is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00708 (1077/152102) while in subpopulation AFR AF= 0.0149 (620/41494). AF 95% confidence interval is 0.014. There are 8 homozygotes in gnomad4. There are 517 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1077 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDB3	NM_001368067.1 linkuse as main transcript	c.349G>A	p.Asp117Asn	missense_variant	6/9	ENST00000263066.11	NP_001354996.1
LDB3	NM_007078.3 linkuse as main transcript	c.690-4823G>A		intron_variant		ENST00000361373.9	NP_009009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000263066.11 linkuse as main transcript	c.349G>A	p.Asp117Asn	missense_variant	6/9	1	NM_001368067.1	ENSP00000263066		O75112-6
LDB3	ENST00000361373.9 linkuse as main transcript	c.690-4823G>A		intron_variant		1	NM_007078.3	ENSP00000355296	P4	O75112-1

Frequencies

GnomAD3 genomes

AF:

0.00710

AC:

1079

AN:

151984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00879

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00333

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.00322

Gnomad OTH

AF:

0.0139

GnomAD3 exomes

AF:

0.00450

AC:

1122

AN:

249184

Hom.:

AF XY:

0.00457

AC XY:

618

AN XY:

135214

show subpopulations

Gnomad AFR exome

AF:

0.0157

Gnomad AMR exome

AF:

0.00542

Gnomad ASJ exome

AF:

0.0104

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00252

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00404

Gnomad OTH exome

AF:

0.00876

GnomAD4 exome

AF:

0.00342

AC:

4996

AN:

1461678

Hom.:

Cov.:

AF XY:

0.00356

AC XY:

2586

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.0170

Gnomad4 AMR exome

AF:

0.00608

Gnomad4 ASJ exome

AF:

0.0101

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00255

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.00278

Gnomad4 OTH exome

AF:

0.00613

GnomAD4 genome

AF:

0.00708

AC:

1077

AN:

152102

Hom.:

Cov.:

AF XY:

0.00695

AC XY:

517

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0149

Gnomad4 AMR

AF:

0.00878

Gnomad4 ASJ

AF:

0.00922

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00334

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00321

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.00470

Hom.:

Bravo

AF:

0.00821

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.0125

AC:

ESP6500EA

AF:

0.00397

AC:

ExAC

AF:

0.00454

AC:

549

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.00567

EpiControl

AF:

0.00729

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:18

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 07, 2013	Asp117Asn in exon 6 of LDB3: This variant is not expected to have clinical signi ficance because it has been identified in 1.3% (51/4090) of African American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS; dbSNP rs121908338). It has been reported in 2 individu als with DCM and 1 individual with LVNC (Vatta 2002, Xi 2012). In vitro studies suggest that it may have functional consequences (Xi 2012), though it should be noted that in vitro studies may not accurately represent biological function and /or may not translate to disease. In summary, the frequency of this variant in the general population suggests that it does not cause disease on its own. It re mains possible that it modifies disease expression. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 02, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:7

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	LDB3: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2018	This variant is associated with the following publications: (PMID: 14662268, 26636822, 26419279, 28416588, 22929165, 23299917, 22995991, 22619057, 27884173, 27896284, 30293248, 30972196, 25214167) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 01, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Dilated cardiomyopathy 1C

Uncertain:2

Uncertain significance, no assertion criteria provided	literature only	OMIM	Dec 03, 2003	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Primary dilated cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Feb 28, 2017	- -

Myofibrillar myopathy 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 11, 2016

This alteration is classified as 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_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

-0.14

Eigen_PC

Benign

0.058

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

D;.;D;D;D

MetaRNN

Benign

0.018

T;T;T;T;T

MetaSVM

Benign

-0.54

MutationTaster

Benign

0.031

A;A;A;A;A;A;A;A;A;A

PROVEAN

Benign

-1.2

N;.;N;N;N

REVEL

Benign

0.27

Sift

Uncertain

0.018

D;.;T;D;T

Sift4G

Benign

0.41

T;T;T;T;T

Polyphen

0.0040, 0.69, 0.30

.;.;B;P;B

Vest4

0.46

MVP

0.78

MPC

0.26

ClinPred

0.027

GERP RS

4.1

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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