LDB3 p.Ala78Thr

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BP6BS1

The NM_007078.3(LDB3):c.2092G>A(p.Ala698Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000495 in 1,613,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A698S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00052 ( 0 hom. )

Consequence

LDB3
NM_007078.3 missense, splice_region

Scores

Splicing: ADA: 0.9587

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 10.0

Publications

20 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):

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

ENSG00000272631 (HGNC:):

ENSG00000272631 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_007078.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 10-86726250-G-A is Benign according to our data. Variant chr10-86726250-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36446.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000236 (36/152264) while in subpopulation NFE AF = 0.000265 (18/68024). AF 95% confidence interval is 0.000171. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007078.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LDB3	NM_007078.3	MANE Select	c.2092G>A	p.Ala698Thr	missense splice_region	Exon 13 of 14	NP_009009.1	O75112-1
LDB3	NM_001171610.2		c.2107G>A	p.Ala703Thr	missense splice_region	Exon 13 of 14	NP_001165081.1	O75112-7
LDB3	NM_001368066.1		c.1951G>A	p.Ala651Thr	missense splice_region	Exon 14 of 15	NP_001354995.1	A0A8I5KV04

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LDB3	ENST00000477489.1	TSL:1	c.232G>A	p.Ala78Thr	missense	Exon 2 of 2	ENSP00000485538.1	A0A096LPD7
LDB3	ENST00000361373.9	TSL:1 MANE Select	c.2092G>A	p.Ala698Thr	missense splice_region	Exon 13 of 14	ENSP00000355296.3	O75112-1
LDB3	ENST00000945680.1		c.2296G>A	p.Ala766Thr	missense splice_region	Exon 13 of 14	ENSP00000615739.1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000235

AC:

AN:

251374

AF XY:

0.000243

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000431

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000522

AC:

762

AN:

1460740

Hom.:

Cov.:

AF XY:

0.000472

AC XY:

343

AN XY:

726738

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33458

American (AMR)

AF:

0.0000895

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.000652

AC:

724

AN:

1111012

Other (OTH)

AF:

0.000265

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

105

140

175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000236

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41564

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68024

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000430

Hom.:

Bravo

AF:

0.000302

EpiCase

AF:

0.000600

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Dilated cardiomyopathy 1C (1)

Myofibrillar myopathy 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.0072

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.025

MetaRNN

Benign

0.35

MetaSVM

Uncertain

0.095

MutationAssessor

Benign

1.1

PhyloP100

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.55

Sift

Benign

0.077

Sift4G

Benign

0.063

Varity_R

0.20

gMVP

0.60

Mutation Taster

=33/67

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.96

dbscSNV1_RF

Pathogenic

0.82

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over