10-86710080-C-G

Position:

• chr10-86710080-C-G

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.1231+30C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0359 in 1,608,826 control chromosomes in the GnomAD database, including 1,286 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (298 hom., cov: 33)
  • Exomes 𝑓: 0.034 (988 hom.)
• Consequence: LDB3 NM_007078.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.212

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 10-86710080-C-G is Benign according to our data. Variant chr10-86710080-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 257339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86710080-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDB3	NM_007078.3	c.1231+30C>G		intron_variant		ENST00000361373.9	NP_009009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9	c.1231+30C>G		intron_variant		1	NM_007078.3	ENSP00000355296.3

Frequencies

GnomAD3 genomes AF: 0.0510 AC: 7761 AN: 152106 Hom.: 295 Cov.: 33

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.0228

Gnomad ASJ AF: 0.0637

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.0209

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0352

Gnomad OTH AF: 0.0407

GnomAD3 exomes AF: 0.0328 AC: 7748 AN: 236054 Hom.: 187 AF XY: 0.0322 AC XY: 4190 AN XY: 129974

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.0190

Gnomad ASJ exome AF: 0.0643

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.0279

Gnomad FIN exome AF: 0.0181

Gnomad NFE exome AF: 0.0339

Gnomad OTH exome AF: 0.0371

GnomAD4 exome AF: 0.0343 AC: 49908 AN: 1456602 Hom.: 988 Cov.: 33 AF XY: 0.0342 AC XY: 24761 AN XY: 724604

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.0195

Gnomad4 ASJ exome AF: 0.0596

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0292

Gnomad4 FIN exome AF: 0.0208

Gnomad4 NFE exome AF: 0.0339

Gnomad4 OTH exome AF: 0.0397

GnomAD4 genome AF: 0.0511 AC: 7784 AN: 152224 Hom.: 298 Cov.: 33 AF XY: 0.0482 AC XY: 3588 AN XY: 74432

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.0227

Gnomad4 ASJ AF: 0.0637

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0239

Gnomad4 FIN AF: 0.0209

Gnomad4 NFE AF: 0.0352

Gnomad4 OTH AF: 0.0460

Alfa AF: 0.0265 Hom.: 20

Bravo AF: 0.0534

Asia WGS AF: 0.0290 AC: 101 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.2
DANN	Benign	0.68

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: rs11597201; hg19: chr10-88469837;