10-86668637-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000372066.8(LDB3):c.-55C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00415 in 1,394,170 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (41 hom.)
• Consequence: LDB3 ENST00000372066.8 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 1.17

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00316 (481/152290) while in subpopulation SAS AF= 0.0108 (52/4824). AF 95% confidence interval is 0.00844. There are 3 homozygotes in gnomad4. There are 246 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 481 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_001368067.1	c.-23-32C>A		intron_variant		ENST00000263066.11
LDB3	NM_007078.3	c.-23-32C>A		intron_variant		ENST00000361373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000263066.11	c.-23-32C>A		intron_variant		1	NM_001368067.1
LDB3	ENST00000361373.9	c.-23-32C>A		intron_variant		1	NM_007078.3	P4

Frequencies

GnomAD3 genomes AF: 0.00316 AC: 481 AN: 152172 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00357

Gnomad OTH AF: 0.00383

GnomAD4 exome AF: 0.00427 AC: 5301 AN: 1241880 Hom.: 41 Cov.: 18 AF XY: 0.00469 AC XY: 2954 AN XY: 629688

Gnomad4 AFR exome AF: 0.000652

Gnomad4 AMR exome AF: 0.00223

Gnomad4 ASJ exome AF: 0.0305

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.0117

Gnomad4 FIN exome AF: 0.0000770

Gnomad4 NFE exome AF: 0.00336

Gnomad4 OTH exome AF: 0.00571

GnomAD4 genome AF: 0.00316 AC: 481 AN: 152290 Hom.: 3 Cov.: 33 AF XY: 0.00330 AC XY: 246 AN XY: 74464

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.0346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0108

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00357

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00302 Hom.: 0

Bravo AF: 0.00292

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Myofibrillar Myopathy, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Myofibrillar myopathy 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated Cardiomyopathy, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Left ventricular noncompaction cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

LDB3: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	14
Dann	Benign	0.76

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs34972863; hg19: chr10-88428394;