10-86668578-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_007078.3(LDB3):c.-24+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.685 in 849,512 control chromosomes in the GnomAD database, including 200,676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.71 ( 39117 hom., cov: 34)

Exomes 𝑓: 0.68 ( 161559 hom. )

Consequence

LDB3
NM_007078.3 splice_region, intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.36

Publications

12 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:

ENSG00000289258 (HGNC:):

ENSG00000289258 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 10-86668578-T-C is Benign according to our data. Variant chr10-86668578-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 138106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_007078.3 link	c.-24+8T>C		splice_region_variant, intron_variant	Intron 1 of 13	ENST00000361373.9	NP_009009.1	O75112-1
LDB3	NM_001368067.1 link	c.-24+8T>C		splice_region_variant, intron_variant	Intron 1 of 8	ENST00000263066.11	NP_001354996.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
LDB3	ENST00000361373.9 link	c.-24+8T>C	splice_region_variant, intron_variant	Intron 1 of 13	1	NM_007078.3	ENSP00000355296.3	O75112-1
LDB3	ENST00000263066.11 link	c.-24+8T>C	splice_region_variant, intron_variant	Intron 1 of 8	1	NM_001368067.1	ENSP00000263066.7	O75112-6
ENSG00000289258	ENST00000443292.2 link	c.1487-91T>C	intron_variant	Intron 11 of 17	1		ENSP00000393132.2	C9JWU6

Frequencies

GnomAD3 genomes

AF:

0.713

AC:

108394

AN:

152120

Hom.:

39067

Cov.:

show subpopulations

Gnomad AFR

AF:

0.816

Gnomad AMI

AF:

0.832

Gnomad AMR

AF:

0.632

Gnomad ASJ

AF:

0.728

Gnomad EAS

AF:

0.806

Gnomad SAS

AF:

0.723

Gnomad FIN

AF:

0.690

Gnomad MID

AF:

0.706

Gnomad NFE

AF:

0.662

Gnomad OTH

AF:

0.665

GnomAD4 exome

AF:

0.679

AC:

473481

AN:

697274

Hom.:

161559

Cov.:

AF XY:

0.679

AC XY:

254191

AN XY:

374114

show subpopulations

African (AFR)

AF:

0.817

AC:

15482

AN:

18956

American (AMR)

AF:

0.591

AC:

24227

AN:

40966

Ashkenazi Jewish (ASJ)

AF:

0.719

AC:

15230

AN:

21190

East Asian (EAS)

AF:

0.804

AC:

28527

AN:

35464

South Asian (SAS)

AF:

0.707

AC:

49166

AN:

69550

European-Finnish (FIN)

AF:

0.690

AC:

30668

AN:

44446

Middle Eastern (MID)

AF:

0.705

AC:

3042

AN:

4312

European-Non Finnish (NFE)

AF:

0.662

AC:

282737

AN:

426866

Other (OTH)

AF:

0.687

AC:

24402

AN:

35524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

8720

17440

26159

34879

43599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.713

AC:

108493

AN:

152238

Hom.:

39117

Cov.:

AF XY:

0.716

AC XY:

53317

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.816

AC:

33927

AN:

41560

American (AMR)

AF:

0.631

AC:

9653

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.728

AC:

2528

AN:

3472

East Asian (EAS)

AF:

0.807

AC:

4179

AN:

5180

South Asian (SAS)

AF:

0.723

AC:

3487

AN:

4824

European-Finnish (FIN)

AF:

0.690

AC:

7312

AN:

10602

Middle Eastern (MID)

AF:

0.701

AC:

206

AN:

294

European-Non Finnish (NFE)

AF:

0.662

AC:

45036

AN:

67992

Other (OTH)

AF:

0.666

AC:

1406

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1652

3304

4956

6608

8260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.626

Hom.:

2037

Bravo

AF:

0.709

Asia WGS

AF:

0.760

AC:

2642

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1C

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Myofibrillar myopathy 4

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Aug 26, 2011

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Left ventricular noncompaction cardiomyopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.046

(source)

DANN

Benign

0.41

PhyloP100

-1.4

PromoterAI

0.021

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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10-86668578-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over