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GeneBe

10-86716548-G-T

Variant summary

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

The NM_007078.3(LDB3):​c.1453G>T​(p.Ala485Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

LDB3
NM_007078.3 missense

Scores

17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.483
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]

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=0.08122155).
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LDB3NM_007078.3 linkuse as main transcriptc.1453G>T p.Ala485Ser missense_variant 10/14 ENST00000361373.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LDB3ENST00000361373.9 linkuse as main transcriptc.1453G>T p.Ala485Ser missense_variant 10/141 NM_007078.3 P4O75112-1

Frequencies

GnomAD3 genomes
AF:
0.0000396
AC:
6
AN:
151508
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
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:
0.0000442
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
249188
Hom.:
0
AF XY:
0.00000741
AC XY:
1
AN XY:
134888
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.0000269
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1461834
Hom.:
0
Cov.:
36
AF XY:
0.0000138
AC XY:
10
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
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:
0.00000989
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000396
AC:
6
AN:
151626
Hom.:
0
Cov.:
31
AF XY:
0.0000270
AC XY:
2
AN XY:
74076
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000197
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000442
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 09, 2014The Ala485Ser variant in LDB3 has been identified by our laboratory in 2 Caucasi an adults with DCM and was absent from large population studies. Computational p rediction tools and conservation analysis do not provide strong support for or a gainst an impact to the protein. In summary, the clinical significance of the Va l30899Gly variant is uncertain. -
Myofibrillar myopathy 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeNov 15, 2022In 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This missense change has been observed in individual(s) with clinical features of LDB3-related conditions (Invitae). This variant is present in population databases (rs397517214, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 485 of the LDB3 protein (p.Ala485Ser). The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.*17174G>T in the primary transcript. -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 11, 2022The c.1453G>T (p.A485S) alteration is located in exon 9 (coding exon 9) of the LDB3 gene. This alteration results from a G to T substitution at nucleotide position 1453, causing the alanine (A) at amino acid position 485 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.067
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
5.6
DANN
Benign
0.97
Eigen
Benign
-0.68
Eigen_PC
Benign
-0.60
FATHMM_MKL
Benign
0.60
D
LIST_S2
Benign
0.76
T;.;T;T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.081
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
0.87
D;D;D;D;D;D
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.49
N;.;N;N
REVEL
Benign
0.020
Sift
Benign
0.39
T;.;T;T
Sift4G
Benign
0.84
T;T;T;T
Polyphen
0.40, 0.0
.;.;B;B
Vest4
0.17
MutPred
0.21
.;.;Gain of glycosylation at A485 (P = 0.0038);.;
MVP
0.57
MPC
0.19
ClinPred
0.058
T
GERP RS
2.2
Varity_R
0.040
gMVP
0.27

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs397517214; hg19: chr10-88476305; API