10-86687054-G-A

Position:

• chr10-86687054-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007078.3(LDB3):​c.690-4842G>A variant causes a 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_007078.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.677

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 -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	Protein	UniProt
LDB3	NM_007078.3	c.690-4842G>A		intron_variant		ENST00000361373.9	NP_009009.1
LDB3	NM_001368067.1	c.345-15G>A		intron_variant		ENST00000263066.11	NP_001354996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9	c.690-4842G>A		intron_variant		1	NM_007078.3	ENSP00000355296.3
LDB3	ENST00000263066.11	c.345-15G>A		intron_variant		1	NM_001368067.1	ENSP00000263066.7
ENSG00000289258	ENST00000443292.2	c.2199-4842G>A		intron_variant		1		ENSP00000393132.2

Frequencies

GnomAD3 genomes AF: 0.0660 AC: 10023 AN: 151774 Hom.: 514 Cov.: 32

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

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.: 32 AF XY: 0.0383 AC XY: 27820 AN XY: 726658

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.: 32 AF XY: 0.0631 AC XY: 4681 AN XY: 74214

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.: 27

Bravo AF: 0.0703

Asia WGS AF: 0.0430 AC: 151 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 19, 2011	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Myofibrillar myopathy 4 Benign:2

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

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

Other links and lift over

dbSNP: rs113445294; hg19: chr10-88446811;