rs138951890

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_007078.3(LDB3):c.1535A>C(p.Gln512Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000788 in 1,613,680 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00067 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00080 ( 1 hom. )

Consequence

LDB3
NM_007078.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:8

Conservation

PhyloP100: 3.40

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=0.009373695).

BP6

Variant 10-86716630-A-C is Benign according to our data. Variant chr10-86716630-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45527.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=3, Uncertain_significance=3}. Variant chr10-86716630-A-C is described in Lovd as [Benign]. Variant chr10-86716630-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000665 (101/151846) while in subpopulation NFE AF= 0.000855 (58/67870). AF 95% confidence interval is 0.000679. There are 0 homozygotes in gnomad4. There are 54 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 101 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_007078.3 link	c.1535A>C	p.Gln512Pro	missense_variant	Exon 10 of 14	ENST00000361373.9	NP_009009.1	O75112-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9 link	c.1535A>C	p.Gln512Pro	missense_variant	Exon 10 of 14	1	NM_007078.3	ENSP00000355296.3		O75112-1

Frequencies

GnomAD3 genomes

AF:

0.000666

AC:

101

AN:

151730

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00350

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000854

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000638

AC:

160

AN:

250676

Hom.:

AF XY:

0.000634

AC XY:

AN XY:

135578

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00314

Gnomad NFE exome

AF:

0.000699

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000801

AC:

1171

AN:

1461834

Hom.:

Cov.:

AF XY:

0.000800

AC XY:

582

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00262

Gnomad4 NFE exome

AF:

0.000871

Gnomad4 OTH exome

AF:

0.000580

GnomAD4 genome

AF:

0.000665

AC:

101

AN:

151846

Hom.:

Cov.:

AF XY:

0.000728

AC XY:

AN XY:

74218

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000209

Gnomad4 FIN

AF:

0.00350

Gnomad4 NFE

AF:

0.000855

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000706

Hom.:

Bravo

AF:

0.000366

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000626

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Apr 26, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24503780, 27896284, 20474083, 23861362, 17097056, 30847666) -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LDB3: BP4 -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 20, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myofibrillar myopathy 4

Benign:2

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary familial dilated cardiomyopathy

Uncertain:1

Aug 29, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Feb 02, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Gln512Pro in exon 12 of LDB3: This variant is not expected to have clinical si gnificance because it has been identified in 0.29% of Finnish chromosomes by the Genome Aggregation Database (gnomAD; http://gnomad.broadinstitute.org; dbSNP rs 138951890). Computational tools predict that this variant impacts protein functi on but this evidence is insufficient to override the high minor allele frequency . ACMG/AMP Criteria applied: BS1, PP3 -

Dilated cardiomyopathy 1C

Benign:1

Aug 16, 2014

Cytogenetics- Mohapatra Lab, Banaras Hindu University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: case-control

- -

Cardiomyopathy

Benign:1

Jan 22, 2018

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Apr 09, 2019

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

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.43

.;.;T;.

Eigen

Benign

0.092

Eigen_PC

Benign

0.19

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.79

T;.;T;T

M_CAP

Benign

0.077

MetaRNN

Benign

0.0094

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.4

.;.;L;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.8

N;.;N;N

REVEL

Benign

0.078

Sift

Benign

0.20

T;.;T;T

Sift4G

Benign

0.41

T;T;T;T

Polyphen

0.023, 0.94

.;.;B;P

Vest4

0.66

MVP

0.76

MPC

0.24

ClinPred

0.059

GERP RS

4.9

Varity_R

0.25

gMVP

0.45

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