10-86668401-T-C

Variant summary

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

The NM_001368064.1(LDB3):c.-23-268T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.753 in 503,232 control chromosomes in the GnomAD database, including 144,526 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.79 (48097 hom., cov: 34)
  • Exomes 𝑓: 0.74 (96429 hom.)
• Consequence: LDB3 NM_001368064.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.148

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=-0.52).
• BP6: Variant 10-86668401-T-C is Benign according to our data. Variant chr10-86668401-T-C is described in ClinVar as [Benign]. Clinvar id is 671123.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.938 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_001368063.1	c.-23-268T>C		intron_variant
LDB3	NM_001368064.1	c.-23-268T>C		intron_variant
LDB3	NM_001368068.1	c.-23-268T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000688001.1	c.-23-268T>C		intron_variant				A2
LDB3	ENST00000688785.1	c.-23-268T>C		intron_variant
LDB3	ENST00000691462.1	c.-23-268T>C		intron_variant
LDB3	ENST00000687856.1	c.-23-268T>C		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.787 AC: 119786 AN: 152110 Hom.: 48028 Cov.: 34

Gnomad AFR AF: 0.946

Gnomad AMI AF: 0.849

Gnomad AMR AF: 0.772

Gnomad ASJ AF: 0.754

Gnomad EAS AF: 0.802

Gnomad SAS AF: 0.804

Gnomad FIN AF: 0.730

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.703

Gnomad OTH AF: 0.761

GnomAD4 exome AF: 0.738 AC: 259110 AN: 351004 Hom.: 96429 Cov.: 0 AF XY: 0.741 AC XY: 137604 AN XY: 185812

Gnomad4 AFR exome AF: 0.942

Gnomad4 AMR exome AF: 0.781

Gnomad4 ASJ exome AF: 0.745

Gnomad4 EAS exome AF: 0.819

Gnomad4 SAS exome AF: 0.793

Gnomad4 FIN exome AF: 0.732

Gnomad4 NFE exome AF: 0.702

Gnomad4 OTH exome AF: 0.743

GnomAD4 genome AF: 0.788 AC: 119914 AN: 152228 Hom.: 48097 Cov.: 34 AF XY: 0.791 AC XY: 58865 AN XY: 74430

Gnomad4 AFR AF: 0.946

Gnomad4 AMR AF: 0.773

Gnomad4 ASJ AF: 0.754

Gnomad4 EAS AF: 0.802

Gnomad4 SAS AF: 0.804

Gnomad4 FIN AF: 0.730

Gnomad4 NFE AF: 0.703

Gnomad4 OTH AF: 0.762

Alfa AF: 0.755 Hom.: 5964

Bravo AF: 0.795

Asia WGS AF: 0.824 AC: 2864 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 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	-0.52
Cadd	Benign	13
Dann	Benign	0.58

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2803555; hg19: chr10-88428158;