rs397517211

Positions:

chr10-86716434-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_007078.3(LDB3):c.1339C>G(p.Pro447Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,578,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P447P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000049 ( 0 hom., cov: 20)

Exomes 𝑓: 0.0000070 ( 0 hom. )

Consequence

LDB3
NM_007078.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.07

Variant links:

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]

LDB3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16956693).

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_007078.3 linkuse as main transcript	c.1339C>G	p.Pro447Ala	missense_variant	10/14	ENST00000361373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000361373.9 linkuse as main transcript	c.1339C>G	p.Pro447Ala	missense_variant	10/14	1	NM_007078.3	P4	O75112-1

Frequencies

GnomAD3 genomes

AF:

0.0000485

AC:

AN:

144304

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000182

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000142

AC:

AN:

211030

Hom.:

AF XY:

0.0000176

AC XY:

AN XY:

113740

show subpopulations

Gnomad AFR exome

AF:

0.000220

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000697

AC:

AN:

1433802

Hom.:

Cov.:

AF XY:

0.00000562

AC XY:

AN XY:

711348

show subpopulations

Gnomad4 AFR exome

AF:

0.000243

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000338

GnomAD4 genome

AF:

0.0000485

AC:

AN:

144304

Hom.:

Cov.:

AF XY:

0.0000286

AC XY:

AN XY:

70030

show subpopulations

Gnomad4 AFR

AF:

0.000182

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 22, 2010

Variant classified as Uncertain Significance - Favor Pathogenic. -

Dilated cardiomyopathy 1C;C4721886:Myofibrillar myopathy 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 08, 2021

- -

Myofibrillar myopathy 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2023

The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.*17060C>G in the primary transcript. This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 447 of the LDB3 protein (p.Pro447Ala). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with LDB3-related conditions. ClinVar contains an entry for this variant (Variation ID: 45516) Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 15, 2022

The p.P447A variant (also known as c.1339C>G), located in coding exon 9 of the LDB3 gene, results from a C to G substitution at nucleotide position 1339. The proline at codon 447 is replaced by alanine, an amino acid with highly similar properties. This alteration was reported in a case of sudden unexplained death and was seen with variants in other cardiac-related genes (Fadel S et al. Acad Forensic Pathol, 2020 Dec;10:166-175). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.32

.;.;T;.

Eigen

Benign

0.046

Eigen_PC

Benign

0.032

FATHMM_MKL

Benign

0.58

LIST_S2

Uncertain

0.89

D;.;T;D

M_CAP

Benign

0.040

MetaRNN

Benign

0.17

T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.1

.;.;M;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.63

N;.;N;N

REVEL

Benign

0.071

Sift

Uncertain

0.014

D;.;D;D

Sift4G

Benign

0.20

T;T;T;T

Polyphen

0.99, 0.74

.;.;D;P

Vest4

0.34

MutPred

0.24

.;.;Loss of relative solvent accessibility (P = 0.0186);.;

MVP

0.78

MPC

0.25

ClinPred

0.088

GERP RS

4.4

Varity_R

0.079

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over