rs35507268

Positions:

chr10-86681466-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_007078.3(LDB3):c.352G>A(p.Val118Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00594 in 1,606,432 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 2 hom., cov: 34)

Exomes 𝑓: 0.0061 ( 32 hom. )

Consequence

LDB3
NM_007078.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 0.0900

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=0.005024433).

BP6

Variant 10-86681466-G-A is Benign according to our data. Variant chr10-86681466-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 45544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86681466-G-A is described in Lovd as [Benign]. Variant chr10-86681466-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00394 (601/152364) while in subpopulation NFE AF= 0.00591 (402/68034). AF 95% confidence interval is 0.00543. There are 2 homozygotes in gnomad4. There are 296 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 601 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDB3	NM_007078.3 linkuse as main transcript	c.352G>A	p.Val118Met	missense_variant	5/14	ENST00000361373.9	NP_009009.1
LDB3	NM_001368067.1 linkuse as main transcript	c.321+1309G>A		intron_variant		ENST00000263066.11	NP_001354996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9 linkuse as main transcript	c.352G>A	p.Val118Met	missense_variant	5/14	1	NM_007078.3	ENSP00000355296	P4	O75112-1
LDB3	ENST00000263066.11 linkuse as main transcript	c.321+1309G>A		intron_variant		1	NM_001368067.1	ENSP00000263066		O75112-6

Frequencies

GnomAD3 genomes

AF:

0.00395

AC:

601

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00414

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00591

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00432

AC:

1042

AN:

241370

Hom.:

AF XY:

0.00434

AC XY:

572

AN XY:

131804

show subpopulations

Gnomad AFR exome

AF:

0.000959

Gnomad AMR exome

AF:

0.00223

Gnomad ASJ exome

AF:

0.00593

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000950

Gnomad FIN exome

AF:

0.00501

Gnomad NFE exome

AF:

0.00685

Gnomad OTH exome

AF:

0.00416

GnomAD4 exome

AF:

0.00614

AC:

8934

AN:

1454068

Hom.:

Cov.:

AF XY:

0.00605

AC XY:

4377

AN XY:

723726

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.00186

Gnomad4 ASJ exome

AF:

0.00613

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000916

Gnomad4 FIN exome

AF:

0.00514

Gnomad4 NFE exome

AF:

0.00728

Gnomad4 OTH exome

AF:

0.00419

GnomAD4 genome

AF:

0.00394

AC:

601

AN:

152364

Hom.:

Cov.:

AF XY:

0.00397

AC XY:

296

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.00509

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00414

Gnomad4 NFE

AF:

0.00591

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00587

Hom.:

Bravo

AF:

0.00363

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00698

AC:

ExAC

AF:

0.00458

AC:

553

EpiCase

AF:

0.00534

EpiControl

AF:

0.00593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

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	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 18, 2015	p.Val118Met in exon 4 of LDB3: This variant is not expected to have clinical sig nificance because it has been identified in 0.7% (455/63354) of European chromos omes including 1 homozygous individual by the Exome Aggregation Consortium (http ://exac.broadinstitute.org/; dbSNP rs35507268). -
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	GeneDx	Feb 06, 2013	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	- -
Likely benign, no assertion criteria provided	research	Blueprint Genetics	Mar 02, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 03, 2015	- -

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
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	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	LDB3: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Feb 26, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 17, 2016	- -

Dilated cardiomyopathy 1C;C4721886:Myofibrillar myopathy 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 25, 2021

- -

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

Oct 25, 2019

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

May 21, 2018

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

0.10

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

.;.;T;T;.;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.073

LIST_S2

Uncertain

0.90

D;.;D;D;D;D

M_CAP

Benign

0.052

MetaRNN

Benign

0.0050

T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

L;L;L;.;L;L

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.53

N;.;N;N;.;N

REVEL

Benign

0.022

Sift

Benign

0.17

T;.;T;T;.;D

Sift4G

Benign

0.22

T;T;T;T;T;T

Polyphen

0.0010, 0.49, 0.42

.;.;B;.;P;B

Vest4

0.22

MVP

0.62

MPC

0.20

ClinPred

0.0053

GERP RS

0.30

Varity_R

0.039

gMVP

0.26

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