rs144445130

chr10-86699293-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001368067.1(LDB3):c.771G>A(p.Thr257=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000638 in 1,611,962 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (4 hom.)
• Consequence: LDB3 NM_001368067.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 3.33

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 10-86699293-G-A is Benign according to our data. Variant chr10-86699293-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43884.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=1, Uncertain_significance=1}. Variant chr10-86699293-G-A is described in Lovd as [Benign]. Variant chr10-86699293-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=3.33 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000516 (78/151292) while in subpopulation SAS AF= 0.00398 (19/4774). AF 95% confidence interval is 0.00261. There are 0 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 78 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_001368067.1	c.771G>A	p.Thr257=	synonymous_variant	9/9	ENST00000263066.11
LDB3	NM_007078.3	c.896+6722G>A		intron_variant		ENST00000361373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000263066.11	c.771G>A	p.Thr257=	synonymous_variant	9/9	1	NM_001368067.1
LDB3	ENST00000361373.9	c.896+6722G>A		intron_variant		1	NM_007078.3	P4

Frequencies

GnomAD3 genomes AF: 0.000516 AC: 78 AN: 151174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000487

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000790

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00398

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000545

Gnomad OTH AF: 0.000483

GnomAD3 exomes AF: 0.000913 AC: 227 AN: 248618 Hom.: 0 AF XY: 0.00106 AC XY: 143 AN XY: 135014

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00324

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.000596

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.000651 AC: 951 AN: 1460670 Hom.: 4 Cov.: 35 AF XY: 0.000756 AC XY: 549 AN XY: 726634

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00299

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00339

Gnomad4 FIN exome AF: 0.0000751

Gnomad4 NFE exome AF: 0.000421

Gnomad4 OTH exome AF: 0.000846

GnomAD4 genome AF: 0.000516 AC: 78 AN: 151292 Hom.: 0 Cov.: 32 AF XY: 0.000623 AC XY: 46 AN XY: 73828

Gnomad4 AFR AF: 0.0000486

Gnomad4 AMR AF: 0.000789

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00398

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000545

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000723 Hom.: 0

Bravo AF: 0.000604

EpiCase AF: 0.000763

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 30, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	LDB3: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:3

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	Apr 04, 2015	p.Thr257Thr in exon 9 of LDB3: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 0.3% (52/16506) of So uth Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs144445130). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 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. -

Myofibrillar myopathy 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2017

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	-0.26
Cadd	Benign	23
Dann	Benign	0.75

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: rs144445130; hg19: chr10-88459050; COSMIC: COSV53938303;