rs397517209

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM4BP6_Very_Strong

The NM_007078.3(LDB3):c.1296_1343delCCCTGCCCCTGCCTACACCCCCTCCCCTGCCCCTGCCTACACCCCCTC(p.Pro433_Ser448del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,607,980 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S432S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

LDB3
NM_007078.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.40

Publications

0 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 -6 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_007078.3.

BP6

Variant 10-86716377-CCCTACACCCCCTCCCCTGCCCCTGCCTACACCCCCTCCCCTGCCCCTG-C is Benign according to our data. Variant chr10-86716377-CCCTACACCCCCTCCCCTGCCCCTGCCTACACCCCCTCCCCTGCCCCTG-C is described in ClinVar as Benign. ClinVar VariationId is 257340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_007078.3 link	c.1296_1343delCCCTGCCCCTGCCTACACCCCCTCCCCTGCCCCTGCCTACACCCCCTC	p.Pro433_Ser448del	disruptive_inframe_deletion	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.1296_1343delCCCTGCCCCTGCCTACACCCCCTCCCCTGCCCCTGCCTACACCCCCTC	p.Pro433_Ser448del	disruptive_inframe_deletion	Exon 10 of 14	1	NM_007078.3	ENSP00000355296.3		O75112-1

Frequencies

GnomAD3 genomes

AF:

0.00000667

AC:

AN:

149866

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000816

AC:

AN:

244960

AF XY:

0.0000601

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.0000549

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.0000826

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000302

AC:

AN:

1458114

Hom.:

AF XY:

0.0000331

AC XY:

AN XY:

725222

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000300

AC:

AN:

33360

American (AMR)

AF:

0.0000897

AC:

AN:

44594

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26066

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.0000814

AC:

AN:

85976

European-Finnish (FIN)

AF:

0.0000565

AC:

AN:

53096

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1111062

Other (OTH)

AF:

0.0000166

AC:

AN:

60164

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.256

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000667

AC:

AN:

149866

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73046

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

40544

American (AMR)

AF:

0.00

AC:

AN:

15020

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3430

East Asian (EAS)

AF:

0.00

AC:

AN:

5076

South Asian (SAS)

AF:

0.00

AC:

AN:

4628

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10466

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67426

Other (OTH)

AF:

0.00

AC:

AN:

2056

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Sep 23, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LDB3 c.1296_1343del48 (p.Ala434_Pro449del) results in an in-frame deletion that is predicted to remove 16 amino acids from the encoded protein. The variant allele was found at a frequency of 8.2e-05 in 244960 control chromosomes. The observed variant frequency is approximately 3.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDB3 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1296_1343del48 in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

Jul 31, 2020

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.4

Mutation Taster

=93/107

disease causing (long InDel)

(source)

Splicing

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

Publications

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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