10-86668279-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001368064.1(LDB3):c.-23-390A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0302 in 152,260 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.030 (85 hom., cov: 33)
• Consequence: LDB3 NM_001368064.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.11

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=-0.79).
• BP6: Variant 10-86668279-A-G is Benign according to our data. Variant chr10-86668279-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 669632.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0302 (4603/152260) while in subpopulation NFE AF= 0.0455 (3097/67998). AF 95% confidence interval is 0.0442. There are 85 homozygotes in gnomad4. There are 2276 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 4604 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_001368063.1	c.-23-390A>G		intron_variant
LDB3	NM_001368064.1	c.-23-390A>G		intron_variant
LDB3	NM_001368068.1	c.-23-390A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000688001.1	c.-23-390A>G		intron_variant				A2
LDB3	ENST00000688785.1	c.-23-390A>G		intron_variant
LDB3	ENST00000691462.1	c.-23-390A>G		intron_variant
LDB3	ENST00000687856.1	c.-23-390A>G		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0303 AC: 4604 AN: 152142 Hom.: 85 Cov.: 33

Gnomad AFR AF: 0.00927

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0247

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.0509

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0455

Gnomad OTH AF: 0.0244

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0302 AC: 4603 AN: 152260 Hom.: 85 Cov.: 33 AF XY: 0.0306 AC XY: 2276 AN XY: 74446

Gnomad4 AFR AF: 0.00924

Gnomad4 AMR AF: 0.0247

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0147

Gnomad4 FIN AF: 0.0509

Gnomad4 NFE AF: 0.0455

Gnomad4 OTH AF: 0.0242

Alfa AF: 0.0377 Hom.: 16

Bravo AF: 0.0262

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely 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	-0.79
Cadd	Benign	12
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: rs34073498; hg19: chr10-88428036;