rs71473272

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001368067.1(LDB3):c.546T>C(p.Ser182=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00444 in 1,613,964 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0035 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0045 ( 44 hom. )

Consequence

LDB3
NM_001368067.1 splice_region, synonymous

Scores

Splicing: ADA: 0.00001666

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:13

Conservation

PhyloP100: -0.424

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 10-86687270-T-C is Benign according to our data. Variant chr10-86687270-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43880.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, Uncertain_significance=4}. Variant chr10-86687270-T-C is described in Lovd as [Likely_benign]. Variant chr10-86687270-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.424 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00352 (536/152202) while in subpopulation SAS AF= 0.0108 (52/4826). AF 95% confidence interval is 0.00844. There are 1 homozygotes in gnomad4. There are 278 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 535 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_001368067.1 linkuse as main transcript	c.546T>C	p.Ser182=	splice_region_variant, synonymous_variant	6/9	ENST00000263066.11
LDB3	NM_007078.3 linkuse as main transcript	c.690-4626T>C		intron_variant		ENST00000361373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000263066.11 linkuse as main transcript	c.546T>C	p.Ser182=	splice_region_variant, synonymous_variant	6/9	1	NM_001368067.1		O75112-6
LDB3	ENST00000361373.9 linkuse as main transcript	c.690-4626T>C		intron_variant		1	NM_007078.3	P4	O75112-1

Frequencies

GnomAD3 genomes

AF:

0.00352

AC:

535

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0106

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00456

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00503

AC:

1253

AN:

249284

Hom.:

AF XY:

0.00589

AC XY:

797

AN XY:

135308

show subpopulations

Gnomad AFR exome

AF:

0.000581

Gnomad AMR exome

AF:

0.00359

Gnomad ASJ exome

AF:

0.0148

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0124

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00484

Gnomad OTH exome

AF:

0.00677

GnomAD4 exome

AF:

0.00453

AC:

6627

AN:

1461762

Hom.:

Cov.:

AF XY:

0.00489

AC XY:

3559

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00407

Gnomad4 ASJ exome

AF:

0.0135

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0122

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.00414

Gnomad4 OTH exome

AF:

0.00535

GnomAD4 genome

AF:

0.00352

AC:

536

AN:

152202

Hom.:

Cov.:

AF XY:

0.00374

AC XY:

278

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.000650

Gnomad4 AMR

AF:

0.00471

Gnomad4 ASJ

AF:

0.0156

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0108

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00456

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00418

Hom.:

Bravo

AF:

0.00345

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 09, 2012	Ser182Ser in exon 6 of LDB3: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and has been identified in 0.3% (22/6920) of European American chromosomes from a broad population by th e NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs714 73272). Ser182Ser in exon 6 of LDB3 (rs71473272; allele frequency = 0.3%, 22/69 20) ** -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	LDB3: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 28, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Myofibrillar myopathy 4

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Myofibrillar Myopathy, Dominant

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated Cardiomyopathy, Dominant

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Left ventricular noncompaction cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated cardiomyopathy 1C

Benign:1

Benign, no assertion criteria provided

case-control

Cytogenetics- Mohapatra Lab, Banaras Hindu University

Jan 30, 2015

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 31, 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

BayesDel_noAF

Benign

-0.76

Cadd

Benign

Dann

Benign

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000017

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.010

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