rs45618633

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000361373.9(LDB3):c.1903G>A(p.Val635Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00433 in 1,614,098 control chromosomes in the GnomAD database, including 187 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V635G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.019 ( 79 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 108 hom. )

Consequence

LDB3
ENST00000361373.9 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 2.47

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009906501).

BP6

Variant 10-86718772-G-A is Benign according to our data. Variant chr10-86718772-G-A is described in ClinVar as [Benign]. Clinvar id is 36445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86718772-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDB3	NM_007078.3 linkuse as main transcript	c.1903G>A	p.Val635Ile	missense_variant	12/14	ENST00000361373.9	NP_009009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9 linkuse as main transcript	c.1903G>A	p.Val635Ile	missense_variant	12/14	1	NM_007078.3	ENSP00000355296	P4	O75112-1

Frequencies

GnomAD3 genomes

AF:

0.0193

AC:

2943

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0647

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00740

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.00521

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.0148

GnomAD3 exomes

AF:

0.00602

AC:

1514

AN:

251446

Hom.:

AF XY:

0.00484

AC XY:

658

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.0634

Gnomad AMR exome

AF:

0.00437

Gnomad ASJ exome

AF:

0.00437

Gnomad EAS exome

AF:

0.00435

Gnomad SAS exome

AF:

0.00389

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000545

Gnomad OTH exome

AF:

0.00440

GnomAD4 exome

AF:

0.00276

AC:

4030

AN:

1461884

Hom.:

108

Cov.:

AF XY:

0.00265

AC XY:

1929

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0679

Gnomad4 AMR exome

AF:

0.00467

Gnomad4 ASJ exome

AF:

0.00494

Gnomad4 EAS exome

AF:

0.00479

Gnomad4 SAS exome

AF:

0.00363

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000396

Gnomad4 OTH exome

AF:

0.00702

GnomAD4 genome

AF:

0.0194

AC:

2952

AN:

152214

Hom.:

Cov.:

AF XY:

0.0189

AC XY:

1407

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.0647

Gnomad4 AMR

AF:

0.00739

Gnomad4 ASJ

AF:

0.00404

Gnomad4 EAS

AF:

0.00522

Gnomad4 SAS

AF:

0.00415

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.00323

Hom.:

Bravo

AF:

0.0211

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0635

AC:

280

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00698

AC:

848

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 07, 2008	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2011	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	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 11, 2016	- -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 31, 2013	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Myofibrillar myopathy 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2015

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

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

.;.;T;.;.

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.023

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

T;.;T;T;T

MetaRNN

Benign

0.0099

T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.5

.;.;L;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.62

N;.;N;N;.

REVEL

Benign

0.17

Sift

Uncertain

0.025

D;.;D;D;.

Sift4G

Uncertain

0.037

D;D;D;D;T

Polyphen

0.80, 0.025

.;.;P;B;.

Vest4

0.30

MVP

0.85

MPC

0.16

ClinPred

0.011

GERP RS

3.6

Varity_R

0.11

gMVP

0.14

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.

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