10-86668546-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_007078.3(LDB3):c.-48G>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 0.11 in 734,816 control chromosomes in the GnomAD database, including 5,320 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.099 (1006 hom., cov: 34)
  • Exomes 𝑓: 0.11 (4314 hom.)
• Consequence: LDB3 NM_007078.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0920

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-86668546-G-A is Benign according to our data. Variant chr10-86668546-G-A is described in ClinVar as [Benign]. Clinvar id is 138104.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_001368067.1	c.-48G>A		5_prime_UTR_variant	1/9	ENST00000263066.11
LDB3	NM_007078.3	c.-48G>A		5_prime_UTR_variant	1/14	ENST00000361373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000263066.11	c.-48G>A		5_prime_UTR_variant	1/9	1	NM_001368067.1
LDB3	ENST00000361373.9	c.-48G>A		5_prime_UTR_variant	1/14	1	NM_007078.3	P4

Frequencies

GnomAD3 genomes AF: 0.0990 AC: 15065 AN: 152156 Hom.: 1007 Cov.: 34

Gnomad AFR AF: 0.0296

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.0248

Gnomad SAS AF: 0.0333

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.112 AC: 65449 AN: 582542 Hom.: 4314 Cov.: 6 AF XY: 0.110 AC XY: 34551 AN XY: 315488

Gnomad4 AFR exome AF: 0.0304

Gnomad4 AMR exome AF: 0.0794

Gnomad4 ASJ exome AF: 0.139

Gnomad4 EAS exome AF: 0.0280

Gnomad4 SAS exome AF: 0.0363

Gnomad4 FIN exome AF: 0.121

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.118

GnomAD4 genome AF: 0.0989 AC: 15058 AN: 152274 Hom.: 1006 Cov.: 34 AF XY: 0.0982 AC XY: 7310 AN XY: 74460

Gnomad4 AFR AF: 0.0295

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.0249

Gnomad4 SAS AF: 0.0332

Gnomad4 FIN AF: 0.120

Gnomad4 NFE AF: 0.139

Gnomad4 OTH AF: 0.110

Alfa AF: 0.0382 Hom.: 34

Bravo AF: 0.0959

Asia WGS AF: 0.0340 AC: 117 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 08, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	13
Dann	Benign	0.83

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2803556; hg19: chr10-88428303; COSMIC: COSV53946901; COSMIC: COSV53946901;