rs45529531

Positions:

• chr10-86691892-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_007078.3(LDB3):​c.690-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,614,060 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 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 0.0042 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (10 hom.)
• Consequence: LDB3 NM_007078.3 splice_region, intron
• Scores: Splicing: ADA: 0.00006169
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:16
• Conservation: PhyloP100: 0.852

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]

ENSG00000289258 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 10-86691892-A-G is Benign according to our data. Variant chr10-86691892-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36448.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4, Benign=9}. Variant chr10-86691892-A-G is described in Lovd as [Benign]. Variant chr10-86691892-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0042 (639/152304) while in subpopulation AMR AF= 0.00915 (140/15306). AF 95% confidence interval is 0.00791. There are 3 homozygotes in gnomad4. There are 293 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 639 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDB3	NM_007078.3	c.690-4A>G		splice_region_variant, intron_variant		ENST00000361373.9	NP_009009.1
LDB3	NM_001368067.1	c.549-4A>G		splice_region_variant, intron_variant		ENST00000263066.11	NP_001354996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9	c.690-4A>G		splice_region_variant, intron_variant		1	NM_007078.3	ENSP00000355296.3
LDB3	ENST00000263066.11	c.549-4A>G		splice_region_variant, intron_variant		1	NM_001368067.1	ENSP00000263066.7
ENSG00000289258	ENST00000443292.2	c.2199-4A>G		splice_region_variant, intron_variant		1		ENSP00000393132.2

Frequencies

GnomAD3 genomes AF: 0.00421 AC: 640 AN: 152186 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00668

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00916

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00270

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00249 AC: 627 AN: 251378 Hom.: 4 AF XY: 0.00233 AC XY: 316 AN XY: 135870

Gnomad AFR exome AF: 0.00708

Gnomad AMR exome AF: 0.00535

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00224

Gnomad OTH exome AF: 0.00570

GnomAD4 exome AF: 0.00245 AC: 3574 AN: 1461756 Hom.: 10 Cov.: 32 AF XY: 0.00234 AC XY: 1700 AN XY: 727178

Gnomad4 AFR exome AF: 0.00717

Gnomad4 AMR exome AF: 0.00530

Gnomad4 ASJ exome AF: 0.00363

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000619

Gnomad4 NFE exome AF: 0.00245

Gnomad4 OTH exome AF: 0.00346

GnomAD4 genome AF: 0.00420 AC: 639 AN: 152304 Hom.: 3 Cov.: 33 AF XY: 0.00393 AC XY: 293 AN XY: 74472

Gnomad4 AFR AF: 0.00666

Gnomad4 AMR AF: 0.00915

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00269

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00289 Hom.: 1

Bravo AF: 0.00492

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00362

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:16

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 05, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 30, 2013	690-4A>G in intron 6 of LDB3: This variant is not expected to have clinical sign ificance because it is not located within the splice consensus sequence and has been identified in 0.7% (30/4406) of African American chromosomes from a broad p opulation by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EV S; dbSNP rs45529531). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 07, 2016	- -

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	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ENSG00000289258: BS2; LDB3: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Myofibrillar myopathy 4 Uncertain:1 Benign:1

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

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 25, 2017	- -
Likely benign, criteria provided, single submitter	curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

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

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 21, 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	-0.72
CADD	Benign	5.6
DANN	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000062
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs45529531; hg19: chr10-88451649;