10-86685628-G-C

Variant names:

• chr10-86685628-G-C
• rs3740345
• NM_007078.3:c.689+3825G>C

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.689+3825G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.719 in 1,606,888 control chromosomes in the GnomAD database, including 419,785 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34777 hom., cov: 32)
  • Exomes 𝑓: 0.72 (385008 hom.)
• Consequence: LDB3 NM_007078.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: -0.492

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=-0.92).
• BP6: Variant 10-86685628-G-C is Benign according to our data. Variant chr10-86685628-G-C is described in ClinVar as [Benign]. Clinvar id is 257337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_007078.3	c.689+3825G>C		intron_variant	Intron 5 of 13	ENST00000361373.9	NP_009009.1
LDB3	NM_001368067.1	c.322-50G>C		intron_variant	Intron 4 of 8	ENST00000263066.11	NP_001354996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9	c.689+3825G>C		intron_variant	Intron 5 of 13	1	NM_007078.3	ENSP00000355296.3
LDB3	ENST00000263066.11	c.322-50G>C		intron_variant	Intron 4 of 8	1	NM_001368067.1	ENSP00000263066.7
ENSG00000289258	ENST00000443292.2	c.2198+3825G>C		intron_variant	Intron 15 of 17	1		ENSP00000393132.2

Frequencies

GnomAD3 genomes AF: 0.670 AC: 101848 AN: 151916 Hom.: 34770 Cov.: 32

Gnomad AFR AF: 0.588

Gnomad AMI AF: 0.757

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.749

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.787

Gnomad FIN AF: 0.641

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.747

Gnomad OTH AF: 0.679

GnomAD3 exomes AF: 0.675 AC: 168369 AN: 249358 Hom.: 58703 AF XY: 0.692 AC XY: 93617 AN XY: 135316

Gnomad AFR exome AF: 0.592

Gnomad AMR exome AF: 0.486

Gnomad ASJ exome AF: 0.747

Gnomad EAS exome AF: 0.457

Gnomad SAS exome AF: 0.796

Gnomad FIN exome AF: 0.647

Gnomad NFE exome AF: 0.744

Gnomad OTH exome AF: 0.695

GnomAD4 exome AF: 0.724 AC: 1052756 AN: 1454854 Hom.: 385008 Cov.: 30 AF XY: 0.727 AC XY: 526907 AN XY: 724346

Gnomad4 AFR exome AF: 0.587

Gnomad4 AMR exome AF: 0.496

Gnomad4 ASJ exome AF: 0.746

Gnomad4 EAS exome AF: 0.462

Gnomad4 SAS exome AF: 0.793

Gnomad4 FIN exome AF: 0.656

Gnomad4 NFE exome AF: 0.744

Gnomad4 OTH exome AF: 0.709

GnomAD4 genome AF: 0.670 AC: 101887 AN: 152034 Hom.: 34777 Cov.: 32 AF XY: 0.665 AC XY: 49389 AN XY: 74298

Gnomad4 AFR AF: 0.588

Gnomad4 AMR AF: 0.575

Gnomad4 ASJ AF: 0.749

Gnomad4 EAS AF: 0.470

Gnomad4 SAS AF: 0.788

Gnomad4 FIN AF: 0.641

Gnomad4 NFE AF: 0.747

Gnomad4 OTH AF: 0.673

Alfa AF: 0.719 Hom.: 7283

Bravo AF: 0.655

Asia WGS AF: 0.617 AC: 2145 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dilated cardiomyopathy 1C Uncertain:1

Sep 11, 2014

Cytogenetics- Mohapatra Lab, Banaras Hindu University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: case-control

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.1
DANN	Benign	0.55

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: rs3740345; hg19: chr10-88445385; COSMIC: COSV53940602;