rs76615432

Positions:

• chr10-86687228-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001368067.1(LDB3):​c.504T>C​(p.Asp168=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.041 in 1,614,128 control chromosomes in the GnomAD database, including 1,920 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (524 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1396 hom.)
• Consequence: LDB3 NM_001368067.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.0400

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=-0.55).
• BP6: Variant 10-86687228-T-C is Benign according to our data. Variant chr10-86687228-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 43879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86687228-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_001368067.1	c.504T>C	p.Asp168=	synonymous_variant	6/9	ENST00000263066.11
LDB3	NM_007078.3	c.690-4668T>C		intron_variant		ENST00000361373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000263066.11	c.504T>C	p.Asp168=	synonymous_variant	6/9	1	NM_001368067.1
LDB3	ENST00000361373.9	c.690-4668T>C		intron_variant		1	NM_007078.3	P4

Frequencies

GnomAD3 genomes AF: 0.0656 AC: 9977 AN: 152148 Hom.: 523 Cov.: 33

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0397

Gnomad ASJ AF: 0.0487

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0304

Gnomad FIN AF: 0.0322

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0376

Gnomad OTH AF: 0.0578

GnomAD3 exomes AF: 0.0392 AC: 9790 AN: 249578 Hom.: 306 AF XY: 0.0377 AC XY: 5104 AN XY: 135402

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.0245

Gnomad ASJ exome AF: 0.0534

Gnomad EAS exome AF: 0.00284

Gnomad SAS exome AF: 0.0369

Gnomad FIN exome AF: 0.0312

Gnomad NFE exome AF: 0.0360

Gnomad OTH exome AF: 0.0439

GnomAD4 exome AF: 0.0384 AC: 56175 AN: 1461862 Hom.: 1396 Cov.: 33 AF XY: 0.0381 AC XY: 27708 AN XY: 727234

Gnomad4 AFR exome AF: 0.149

Gnomad4 AMR exome AF: 0.0251

Gnomad4 ASJ exome AF: 0.0526

Gnomad4 EAS exome AF: 0.00149

Gnomad4 SAS exome AF: 0.0354

Gnomad4 FIN exome AF: 0.0350

Gnomad4 NFE exome AF: 0.0363

Gnomad4 OTH exome AF: 0.0468

GnomAD4 genome AF: 0.0656 AC: 9995 AN: 152266 Hom.: 524 Cov.: 33 AF XY: 0.0618 AC XY: 4601 AN XY: 74470

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.0395

Gnomad4 ASJ AF: 0.0487

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.0307

Gnomad4 FIN AF: 0.0322

Gnomad4 NFE AF: 0.0376

Gnomad4 OTH AF: 0.0577

Alfa AF: 0.0541 Hom.: 180

Bravo AF: 0.0686

Asia WGS AF: 0.0500 AC: 174 AN: 3478

EpiCase AF: 0.0397

EpiControl AF: 0.0393

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 21, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 09, 2011	This variant is classified as benign based on its high frequency in control popu lations (18% in Blacks and 4% in Caucasians; LMM unpublished data). -

Dilated cardiomyopathy 1C Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	case-control	Cytogenetics- Mohapatra Lab, Banaras Hindu University	Sep 11, 2014	- -

Myofibrillar myopathy 4 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Myofibrillar Myopathy, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated Cardiomyopathy, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2015

This alteration is classified as 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	-0.55
CADD	Benign	7.4
DANN	Benign	0.51

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: rs76615432; hg19: chr10-88446985; COSMIC: COSV53937916;