10-86668578-T-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.-24+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.685 in 849,512 control chromosomes in the GnomAD database, including 200,676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (39117 hom., cov: 34)
  • Exomes 𝑓: 0.68 (161559 hom.)
• Consequence: LDB3 NM_007078.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.36

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=-0.85).
• BP6: Variant 10-86668578-T-C is Benign according to our data. Variant chr10-86668578-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 138106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_001368067.1	c.-24+8T>C		splice_region_variant, intron_variant		ENST00000263066.11
LDB3	NM_007078.3	c.-24+8T>C		splice_region_variant, intron_variant		ENST00000361373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000263066.11	c.-24+8T>C		splice_region_variant, intron_variant		1	NM_001368067.1
LDB3	ENST00000361373.9	c.-24+8T>C		splice_region_variant, intron_variant		1	NM_007078.3	P4

Frequencies

GnomAD3 genomes AF: 0.713 AC: 108394 AN: 152120 Hom.: 39067 Cov.: 34

Gnomad AFR AF: 0.816

Gnomad AMI AF: 0.832

Gnomad AMR AF: 0.632

Gnomad ASJ AF: 0.728

Gnomad EAS AF: 0.806

Gnomad SAS AF: 0.723

Gnomad FIN AF: 0.690

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.662

Gnomad OTH AF: 0.665

GnomAD4 exome AF: 0.679 AC: 473481 AN: 697274 Hom.: 161559 Cov.: 9 AF XY: 0.679 AC XY: 254191 AN XY: 374114

Gnomad4 AFR exome AF: 0.817

Gnomad4 AMR exome AF: 0.591

Gnomad4 ASJ exome AF: 0.719

Gnomad4 EAS exome AF: 0.804

Gnomad4 SAS exome AF: 0.707

Gnomad4 FIN exome AF: 0.690

Gnomad4 NFE exome AF: 0.662

Gnomad4 OTH exome AF: 0.687

GnomAD4 genome AF: 0.713 AC: 108493 AN: 152238 Hom.: 39117 Cov.: 34 AF XY: 0.716 AC XY: 53317 AN XY: 74440

Gnomad4 AFR AF: 0.816

Gnomad4 AMR AF: 0.631

Gnomad4 ASJ AF: 0.728

Gnomad4 EAS AF: 0.807

Gnomad4 SAS AF: 0.723

Gnomad4 FIN AF: 0.690

Gnomad4 NFE AF: 0.662

Gnomad4 OTH AF: 0.666

Alfa AF: 0.626 Hom.: 2037

Bravo AF: 0.709

Asia WGS AF: 0.760 AC: 2642 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1C Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 26, 2011

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. -

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	-0.85
Cadd	Benign	0.046
Dann	Benign	0.41

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2803558; hg19: chr10-88428335;