rs757728320

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_007078.3(LDB3):c.1321C>T(p.Pro441Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000645 in 1,549,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 20)

Exomes 𝑓: 0.0000057 ( 0 hom. )

Consequence

LDB3
NM_007078.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.59

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

myofibrillar myopathy 4
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
familial dilated cardiomyopathy
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

LDB3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19654739).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_007078.3 link	c.1321C>T	p.Pro441Ser	missense_variant	Exon 10 of 14	ENST00000361373.9	NP_009009.1	O75112-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9 link	c.1321C>T	p.Pro441Ser	missense_variant	Exon 10 of 14	1	NM_007078.3	ENSP00000355296.3		O75112-1

Frequencies

GnomAD3 genomes

AF:

0.0000141

AC:

AN:

142020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000265

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:

0.0000154

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000559

AC:

AN:

179028

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000139

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000568

AC:

AN:

1407636

Hom.:

Cov.:

AF XY:

0.00000575

AC XY:

AN XY:

695766

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32452

American (AMR)

AF:

0.00

AC:

AN:

38528

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25146

East Asian (EAS)

AF:

0.00

AC:

AN:

37606

South Asian (SAS)

AF:

0.00

AC:

AN:

80832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49640

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4052

European-Non Finnish (NFE)

AF:

0.00000740

AC:

AN:

1081144

Other (OTH)

AF:

0.00

AC:

AN:

58236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.588

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000141

AC:

AN:

142020

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

68806

show subpopulations

African (AFR)

AF:

0.0000265

AC:

AN:

37786

American (AMR)

AF:

0.00

AC:

AN:

14114

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3356

East Asian (EAS)

AF:

0.00

AC:

AN:

4746

South Asian (SAS)

AF:

0.00

AC:

AN:

4136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9870

Middle Eastern (MID)

AF:

0.00

AC:

AN:

296

European-Non Finnish (NFE)

AF:

0.0000154

AC:

AN:

64936

Other (OTH)

AF:

0.00

AC:

AN:

1908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000257

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Myofibrillar myopathy 4

Uncertain:1

Oct 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 429038). The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.*17042C>T in the primary transcript. This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 441 of the LDB3 protein (p.Pro441Ser). 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 missense change has been observed in individual(s) with idiopathic ventricular fibrillation (PMID: 29032884). This variant is also known as p.Pro446Ser. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

.;.;T;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.59

LIST_S2

Uncertain

0.86

D;.;D;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.20

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.2

.;.;M;.

PhyloP100

1.6

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.8

N;.;N;N

REVEL

Benign

0.10

Sift

Benign

0.25

T;.;T;T

Sift4G

Benign

0.13

T;T;T;T

Polyphen

0.95, 0.15

.;.;P;B

Vest4

0.31

MutPred

0.24

.;.;Gain of phosphorylation at P441 (P = 0.0178);.;

MVP

0.68

MPC

0.76

ClinPred

0.35

GERP RS

4.5

Varity_R

0.083

gMVP

0.34

Mutation Taster

=78/22

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs757728320

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over