rs45543741

chr10-86681690-G-Achr10-86681690-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_007078.3(LDB3):c.576G>A(p.Pro192=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000423 in 1,613,638 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P192P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00022 (3 hom.)
• Consequence: LDB3 NM_007078.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.887

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 10-86681690-G-A is Benign according to our data. Variant chr10-86681690-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 45547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86681690-G-A is described in Lovd as [Benign]. Variant chr10-86681690-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.887 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00236 (359/152362) while in subpopulation AFR AF= 0.00755 (314/41586). AF 95% confidence interval is 0.00686. There are 1 homozygotes in gnomad4. There are 176 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd at 359 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_007078.3	c.576G>A	p.Pro192=	synonymous_variant	5/14	ENST00000361373.9
LDB3	NM_001368067.1	c.321+1533G>A		intron_variant		ENST00000263066.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000361373.9	c.576G>A	p.Pro192=	synonymous_variant	5/14	1	NM_007078.3	P4
LDB3	ENST00000263066.11	c.321+1533G>A		intron_variant		1	NM_001368067.1

Frequencies

GnomAD3 genomes AF: 0.00236 AC: 359 AN: 152244 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00757

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000603 AC: 151 AN: 250612 Hom.: 1 AF XY: 0.000420 AC XY: 57 AN XY: 135704

Gnomad AFR exome AF: 0.00802

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000222 AC: 324 AN: 1461276 Hom.: 3 Cov.: 32 AF XY: 0.000194 AC XY: 141 AN XY: 726926

Gnomad4 AFR exome AF: 0.00684

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.00236 AC: 359 AN: 152362 Hom.: 1 Cov.: 34 AF XY: 0.00236 AC XY: 176 AN XY: 74508

Gnomad4 AFR AF: 0.00755

Gnomad4 AMR AF: 0.000718

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.0000425 Hom.: 0

Bravo AF: 0.00277

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 29, 2010	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 16, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 18, 2016	Variant summary: The c.576G>A variant affects a non-conserved nucleotide, resulting in synonymous amino acid change. 5/5 in silico programs via Alamut predict that this variant does not affect normal splicing. This variant is found in 87/119636 control chromosomes from the large and broad populations of ExAC at a frequency of 0.0007272, which is about 29 times greater than the maximal expected frequency of a pathogenic allele (0.000025), suggesting this variant is benign. In addition, multiple clinical laboratories have classified this variant as benign. One internal sample carrying this variant was also found to carry a pathogenic variant in TTR gene (p.V142I) further supporting benign outcome. Taken together, this variant has been classified as Benign. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 26, 2017

- -

Myofibrillar myopathy 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.93
Dann	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs45543741; hg19: chr10-88441447;