rs45555240

chr10-86706675-C-Achr10-86706675-C-T

Variant summary

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

The NM_007078.3(LDB3):c.1041C>A(p.Ser347=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00937 in 1,612,904 control chromosomes in the GnomAD database, including 1,106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S347S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.046 (561 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (545 hom.)
• Consequence: LDB3 NM_007078.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:9
• Conservation: PhyloP100: -0.819

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=-0.8).
• BP6: Variant 10-86706675-C-A is Benign according to our data. Variant chr10-86706675-C-A is described in ClinVar as [Benign]. Clinvar id is 36442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86706675-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.819 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_007078.3	c.1041C>A	p.Ser347=	synonymous_variant	8/14	ENST00000361373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000361373.9	c.1041C>A	p.Ser347=	synonymous_variant	8/14	1	NM_007078.3	P4

Frequencies

GnomAD3 genomes AF: 0.0462 AC: 7035 AN: 152194 Hom.: 559 Cov.: 33

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0199

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0128 AC: 3184 AN: 247946 Hom.: 221 AF XY: 0.00963 AC XY: 1297 AN XY: 134752

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.00855

Gnomad ASJ exome AF: 0.00433

Gnomad EAS exome AF: 0.00435

Gnomad SAS exome AF: 0.00422

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000522

Gnomad OTH exome AF: 0.00694

GnomAD4 exome AF: 0.00552 AC: 8068 AN: 1460592 Hom.: 545 Cov.: 32 AF XY: 0.00492 AC XY: 3574 AN XY: 726632

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.00494

Gnomad4 EAS exome AF: 0.00479

Gnomad4 SAS exome AF: 0.00404

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000389

Gnomad4 OTH exome AF: 0.0136

GnomAD4 genome AF: 0.0463 AC: 7051 AN: 152312 Hom.: 561 Cov.: 33 AF XY: 0.0443 AC XY: 3298 AN XY: 74494

Gnomad4 AFR AF: 0.157

Gnomad4 AMR AF: 0.0199

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00521

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.0341

Alfa AF: 0.00314 Hom.: 1

Bravo AF: 0.0524

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000890

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 29, 2019	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 24, 2008	- -

Dilated cardiomyopathy 1C Uncertain:1

Uncertain significance, no assertion criteria provided

case-control

Cytogenetics- Mohapatra Lab, Banaras Hindu University

Feb 10, 2015

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

Myofibrillar myopathy 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 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	-0.80
Cadd	Benign	0.23
Dann	Benign	0.67

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: rs45555240; hg19: chr10-88466432;