rs3740343

Positions:

chr10-86679436-G-A

Variant summary

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

The NM_007078.3(LDB3):c.163G>A(p.Val55Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00233 in 1,614,106 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 14 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 113 hom. )

Consequence

LDB3
NM_007078.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 3.58

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:

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=0.0027198195).

BP6

Variant 10-86679436-G-A is Benign according to our data. Variant chr10-86679436-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 45530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86679436-G-A is described in Lovd as [Benign]. Variant chr10-86679436-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDB3	NM_007078.3 link	c.163G>A	p.Val55Ile	missense_variant	3/14	ENST00000361373.9	NP_009009.1	O75112-1
LDB3	NM_001368067.1 link	c.163G>A	p.Val55Ile	missense_variant	3/9	ENST00000263066.11	NP_001354996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LDB3	ENST00000361373.9 link	c.163G>A	p.Val55Ile	missense_variant	3/14	1	NM_007078.3	ENSP00000355296.3	O75112-1
LDB3	ENST00000263066.11 link	c.163G>A	p.Val55Ile	missense_variant	3/9	1	NM_001368067.1	ENSP00000263066.7	O75112-6
ENSG00000289258	ENST00000443292.2 link	c.1672G>A	p.Val558Ile	missense_variant	13/18	1		ENSP00000393132.2	C9JWU6

Frequencies

GnomAD3 genomes

AF:

0.00383

AC:

583

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.0790

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00782

AC:

1967

AN:

251402

Hom.:

AF XY:

0.00729

AC XY:

990

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.000985

Gnomad AMR exome

AF:

0.00538

Gnomad ASJ exome

AF:

0.00605

Gnomad EAS exome

AF:

0.0869

Gnomad SAS exome

AF:

0.00173

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000264

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00217

AC:

3179

AN:

1461842

Hom.:

113

Cov.:

AF XY:

0.00214

AC XY:

1553

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00510

Gnomad4 ASJ exome

AF:

0.00532

Gnomad4 EAS exome

AF:

0.0569

Gnomad4 SAS exome

AF:

0.00157

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000953

Gnomad4 OTH exome

AF:

0.00485

GnomAD4 genome

AF:

0.00383

AC:

583

AN:

152264

Hom.:

Cov.:

AF XY:

0.00411

AC XY:

306

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000770

Gnomad4 AMR

AF:

0.00536

Gnomad4 ASJ

AF:

0.00547

Gnomad4 EAS

AF:

0.0790

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.000766

Hom.:

Bravo

AF:

0.00515

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00723

AC:

878

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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	Jan 19, 2009	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 02, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Myofibrillar myopathy 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2018	This variant is associated with the following publications: (PMID: 27553890) -

Dilated cardiomyopathy 1C

Benign:1

Likely benign, 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Myofibrillar Myopathy, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Feb 26, 2016

- -

Dilated cardiomyopathy 1C;C4721886:Myofibrillar myopathy 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 20, 2021

- -

Dilated Cardiomyopathy, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 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

0.061

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.082

.;.;.;T;T;.;.;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.047

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.79

T;.;T;T;T;T;T;T

MetaRNN

Benign

0.0027

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.31

N;N;N;N;.;N;N;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.080

N;.;N;N;N;.;N;N

REVEL

Benign

0.042

Sift

Benign

0.95

T;.;T;T;T;.;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T;T;T

Polyphen

0.44, 0.13, 0.96, 0.28, 0.030

.;.;B;B;.;D;B;B

Vest4

0.69

MVP

0.48

MPC

0.18

ClinPred

0.013

GERP RS

3.8

Varity_R

0.11

gMVP

0.21

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