rs3740346

chr10-86692112-G-Cchr10-86692112-G-T

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.859+47G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,605,672 control chromosomes in the GnomAD database, including 22,751 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2394 hom., cov: 33)
  • Exomes 𝑓: 0.14 (20357 hom.)
• Consequence: LDB3 NM_007078.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: 0.337

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-86692112-G-C is Benign according to our data. Variant chr10-86692112-G-C is described in ClinVar as [Benign]. Clinvar id is 257338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_001368067.1	c.718+47G>C		intron_variant		ENST00000263066.11
LDB3	NM_007078.3	c.859+47G>C		intron_variant		ENST00000361373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000263066.11	c.718+47G>C		intron_variant		1	NM_001368067.1
LDB3	ENST00000361373.9	c.859+47G>C		intron_variant		1	NM_007078.3	P4

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21975 AN: 152076 Hom.: 2399 Cov.: 33

Gnomad AFR AF: 0.0881

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.627

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.137

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.139

GnomAD3 exomes AF: 0.192 AC: 46530 AN: 242028 Hom.: 6728 AF XY: 0.186 AC XY: 24368 AN XY: 131188

Gnomad AFR exome AF: 0.0865

Gnomad AMR exome AF: 0.269

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.643

Gnomad SAS exome AF: 0.161

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.123

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.141 AC: 204955 AN: 1453478 Hom.: 20357 Cov.: 30 AF XY: 0.141 AC XY: 101950 AN XY: 723028

Gnomad4 AFR exome AF: 0.0817

Gnomad4 AMR exome AF: 0.260

Gnomad4 ASJ exome AF: 0.160

Gnomad4 EAS exome AF: 0.619

Gnomad4 SAS exome AF: 0.161

Gnomad4 FIN exome AF: 0.185

Gnomad4 NFE exome AF: 0.116

Gnomad4 OTH exome AF: 0.160

GnomAD4 genome AF: 0.144 AC: 21970 AN: 152194 Hom.: 2394 Cov.: 33 AF XY: 0.153 AC XY: 11388 AN XY: 74398

Gnomad4 AFR AF: 0.0880

Gnomad4 AMR AF: 0.200

Gnomad4 ASJ AF: 0.160

Gnomad4 EAS AF: 0.626

Gnomad4 SAS AF: 0.185

Gnomad4 FIN AF: 0.193

Gnomad4 NFE AF: 0.118

Gnomad4 OTH AF: 0.138

Alfa AF: 0.134 Hom.: 290

Bravo AF: 0.147

Asia WGS AF: 0.355 AC: 1231 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1C Uncertain:1

Uncertain significance, no assertion criteria provided

case-control

Cytogenetics- Mohapatra Lab, Banaras Hindu University

Aug 19, 2014

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	4.2
Dann	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs3740346; hg19: chr10-88451869;