rs142625982

chr10-86716517-G-Achr10-86716517-G-Cchr10-86716517-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.1422G>A(p.Ser474=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,610,926 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0024 (7 hom.)
• Consequence: LDB3 NM_007078.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.40

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=-0.91).
• BP6: Variant 10-86716517-G-A is Benign according to our data. Variant chr10-86716517-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86716517-G-A is described in Lovd as [Benign]. Variant chr10-86716517-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.4 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00139 (208/149260) while in subpopulation NFE AF= 0.00221 (149/67360). AF 95% confidence interval is 0.00192. There are 1 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 208 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_007078.3	c.1422G>A	p.Ser474=	synonymous_variant	10/14	ENST00000361373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000361373.9	c.1422G>A	p.Ser474=	synonymous_variant	10/14	1	NM_007078.3	P4

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 208 AN: 149148 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000695

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000403

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000200

Gnomad SAS AF: 0.000430

Gnomad FIN AF: 0.00206

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00221

Gnomad OTH AF: 0.000486

GnomAD3 exomes AF: 0.00107 AC: 266 AN: 248768 Hom.: 0 AF XY: 0.00103 AC XY: 139 AN XY: 134726

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00181

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.00245 AC: 3581 AN: 1461666 Hom.: 7 Cov.: 36 AF XY: 0.00236 AC XY: 1713 AN XY: 727102

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000672

Gnomad4 FIN exome AF: 0.000618

Gnomad4 NFE exome AF: 0.00296

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.00139 AC: 208 AN: 149260 Hom.: 1 Cov.: 30 AF XY: 0.00127 AC XY: 92 AN XY: 72622

Gnomad4 AFR AF: 0.000693

Gnomad4 AMR AF: 0.000403

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000200

Gnomad4 SAS AF: 0.000431

Gnomad4 FIN AF: 0.00206

Gnomad4 NFE AF: 0.00221

Gnomad4 OTH AF: 0.000481

Alfa AF: 0.00177 Hom.: 0

Bravo AF: 0.00120

EpiCase AF: 0.00262

EpiControl AF: 0.00213

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	LDB3: BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:4

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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 19, 2017	Variant summary: The LDB3 c.1422G>A (p.Ser474Ser) variant involves the alteration of a non-conserved nucleotide causing a synonymous change that 4/5 splice prediction tools predict change of a cryptic splicing acceptor site. ESE finder predicts that this variant may alter ESE binding. However, these predictions have yet to be confirmed by functional studies. This variant was found in 301/264076 control chromosomes (gnomAD) at a frequency of 0.0011398, which is approximately 46 times the estimated maximal expected allele frequency of a pathogenic LDB3 variant (0.000025), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories classified this variant as likely benign/benign. Therefore, due to the nature and location of this variant, control population frequency, and additional clinical diagnostic laboratories classifying the variant as "likely benign/benign," the variant of interest has been classified as Benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 18, 2015	p.Ser474Ser in exon 12 of LDB3: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 0.1% (91/66282) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs142625982). -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jan 26, 2018

- -

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

Dec 15, 2015

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	-0.91
Cadd	Benign	4.7
Dann	Benign	0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.46		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs142625982; hg19: chr10-88476274;