rs113445294

Variant summary

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

The NM_001368067.1(LDB3):c.345-15G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0411 in 1,612,666 control chromosomes in the GnomAD database, including 1,914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.066 ( 517 hom., cov: 32)

Exomes 𝑓: 0.038 ( 1397 hom. )

Consequence

LDB3
NM_001368067.1 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.677

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 (BayesDel_noAF=-0.88).

BP6

Variant 10-86687054-G-A is Benign according to our data. Variant chr10-86687054-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 43875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86687054-G-A is described in Lovd as [Benign]. Variant chr10-86687054-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_001368067.1 linkuse as main transcript	c.345-15G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000263066.11
LDB3	NM_007078.3 linkuse as main transcript	c.690-4842G>A		intron_variant		ENST00000361373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000263066.11 linkuse as main transcript	c.345-15G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001368067.1		O75112-6
LDB3	ENST00000361373.9 linkuse as main transcript	c.690-4842G>A		intron_variant		1	NM_007078.3	P4	O75112-1

Frequencies

GnomAD3 genomes

AF:

0.0660

AC:

10023

AN:

151774

Hom.:

514

Cov.:

show subpopulations

Gnomad AFR

AF:

0.146

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0407

Gnomad ASJ

AF:

0.0488

Gnomad EAS

AF:

0.00193

Gnomad SAS

AF:

0.0312

Gnomad FIN

AF:

0.0324

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0375

Gnomad OTH

AF:

0.0643

GnomAD3 exomes

AF:

0.0398

AC:

9911

AN:

248846

Hom.:

330

AF XY:

0.0385

AC XY:

5196

AN XY:

135028

show subpopulations

Gnomad AFR exome

AF:

0.150

Gnomad AMR exome

AF:

0.0251

Gnomad ASJ exome

AF:

0.0533

Gnomad EAS exome

AF:

0.00284

Gnomad SAS exome

AF:

0.0371

Gnomad FIN exome

AF:

0.0312

Gnomad NFE exome

AF:

0.0360

Gnomad OTH exome

AF:

0.0440

GnomAD4 exome

AF:

0.0385

AC:

56205

AN:

1460776

Hom.:

1397

Cov.:

AF XY:

0.0383

AC XY:

27820

AN XY:

726658

show subpopulations

Gnomad4 AFR exome

AF:

0.153

Gnomad4 AMR exome

AF:

0.0256

Gnomad4 ASJ exome

AF:

0.0526

Gnomad4 EAS exome

AF:

0.00149

Gnomad4 SAS exome

AF:

0.0355

Gnomad4 FIN exome

AF:

0.0350

Gnomad4 NFE exome

AF:

0.0362

Gnomad4 OTH exome

AF:

0.0472

GnomAD4 genome

AF:

0.0662

AC:

10052

AN:

151890

Hom.:

517

Cov.:

AF XY:

0.0631

AC XY:

4681

AN XY:

74214

show subpopulations

Gnomad4 AFR

AF:

0.146

Gnomad4 AMR

AF:

0.0405

Gnomad4 ASJ

AF:

0.0488

Gnomad4 EAS

AF:

0.00193

Gnomad4 SAS

AF:

0.0312

Gnomad4 FIN

AF:

0.0324

Gnomad4 NFE

AF:

0.0375

Gnomad4 OTH

AF:

0.0642

Alfa

AF:

0.0302

Hom.:

Bravo

AF:

0.0703

Asia WGS

AF:

0.0430

AC:

151

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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	Sep 19, 2011	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Myofibrillar myopathy 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Dilated cardiomyopathy 1C

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Myofibrillar Myopathy, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Left ventricular noncompaction cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

Cadd

Benign

0.87

Dann

Benign

0.67

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