rs139922045

Variant names:

• chr10-86681778-G-A
• rs139922045
• NM_007078.3:c.664G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_007078.3(LDB3):​c.664G>A​(p.Ala222Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000378 in 1,598,880 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00038 (2 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: 2.84
• Publications: 8 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 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

ENSG00000289258 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05650574).
• BP6: Variant 10-86681778-G-A is Benign according to our data. Variant chr10-86681778-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45551.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000348 (53/152342) while in subpopulation NFE AF = 0.000764 (52/68036). AF 95% confidence interval is 0.000598. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB3	NM_007078.3	MANE Select	c.664G>A	p.Ala222Thr	missense	Exon 5 of 14	NP_009009.1	O75112-1
	LDB3	NM_001368067.1	MANE Plus Clinical	c.321+1621G>A		intron	N/A	NP_001354996.1	A0A0S2Z530
	LDB3	NM_001171610.2		c.664G>A	p.Ala222Thr	missense	Exon 5 of 14	NP_001165081.1	O75112-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB3	ENST00000361373.9	TSL:1 MANE Select	c.664G>A	p.Ala222Thr	missense	Exon 5 of 14	ENSP00000355296.3	O75112-1
	ENSG00000289258	ENST00000443292.2	TSL:1	c.2173G>A	p.Ala725Thr	missense	Exon 15 of 18	ENSP00000393132.2	C9JWU6
	LDB3	ENST00000372056.8	TSL:1	c.664G>A	p.Ala222Thr	missense	Exon 4 of 8	ENSP00000361126.4	O75112-4

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152224 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

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: 0.000764

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000351 AC: 84 AN: 239460 AF XY: 0.000371

Gnomad AFR exome AF: 0.0000629

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000111

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000476

Gnomad NFE exome AF: 0.000713

Gnomad OTH exome AF: 0.000348

GnomAD4 exome AF: 0.000381 AC: 551 AN: 1446538 Hom.: 2 Cov.: 32 AF XY: 0.000386 AC XY: 277 AN XY: 717838

African (AFR) AF: 0.0000608 AC: 2 AN: 32920

American (AMR) AF: 0.00 AC: 0 AN: 42744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25280

East Asian (EAS) AF: 0.00 AC: 0 AN: 39496

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83764

European-Finnish (FIN) AF: 0.0000764 AC: 4 AN: 52344

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5700

European-Non Finnish (NFE) AF: 0.000481 AC: 531 AN: 1104634

Other (OTH) AF: 0.000201 AC: 12 AN: 59656

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152342 Hom.: 0 Cov.: 34 AF XY: 0.000349 AC XY: 26 AN XY: 74496

African (AFR) AF: 0.0000240 AC: 1 AN: 41592

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000764 AC: 52 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000712 Hom.: 1

Bravo AF: 0.000374

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000387 AC: 47

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	1	not specified (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1C;C4721886:Myofibrillar myopathy 4 (1)
-	-	1	LDB3-related disorder (1)
-	-	1	Myofibrillar myopathy 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Benign	0.026
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.8
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.095
Sift	Benign	0.24	T
Sift4G	Benign	0.37	T
Polyphen		0.0010	B
Vest4		0.24
MVP		0.72
MPC		0.20
ClinPred		0.068	T
GERP RS		3.7
Varity_R		0.11
gMVP		0.61
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs139922045; hg19: chr10-88441535;