rs34423165

Variant names:

• chr10-86691958-A-G
• rs34423165
• NM_007078.3:c.752A>G
• LDB3 p.Lys251Arg

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007078.3(LDB3):​c.752A>G​(p.Lys251Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00468 in 1,614,166 control chromosomes in the GnomAD database, including 174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (75 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (99 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:18
• Conservation: PhyloP100: 4.14
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034063756).
• BP6: Variant 10-86691958-A-G is Benign according to our data. Variant chr10-86691958-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0521 is higher than 0.05.

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.752A>G	p.Lys251Arg	missense	Exon 6 of 14	NP_009009.1	O75112-1
	LDB3	NM_001368067.1	MANE Plus Clinical	c.611A>G	p.Lys204Arg	missense	Exon 7 of 9	NP_001354996.1	A0A0S2Z530
	LDB3	NM_001171610.2		c.956A>G	p.Lys319Arg	missense	Exon 7 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.752A>G	p.Lys251Arg	missense	Exon 6 of 14	ENSP00000355296.3	O75112-1
	LDB3	ENST00000263066.11	TSL:1 MANE Plus Clinical	c.611A>G	p.Lys204Arg	missense	Exon 7 of 9	ENSP00000263066.7	O75112-6
	ENSG00000289258	ENST00000443292.2	TSL:1	c.2261A>G	p.Lys754Arg	missense	Exon 16 of 18	ENSP00000393132.2	C9JWU6

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 2390 AN: 152202 Hom.: 75 Cov.: 33

Gnomad AFR AF: 0.0510

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00592 AC: 1489 AN: 251466 AF XY: 0.00536

Gnomad AFR exome AF: 0.0485

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00147

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00352 AC: 5153 AN: 1461846 Hom.: 99 Cov.: 32 AF XY: 0.00363 AC XY: 2641 AN XY: 727224

African (AFR) AF: 0.0542 AC: 1814 AN: 33476

American (AMR) AF: 0.00362 AC: 162 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00333 AC: 87 AN: 26136

East Asian (EAS) AF: 0.000680 AC: 27 AN: 39700

South Asian (SAS) AF: 0.0103 AC: 890 AN: 86252

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53386

Middle Eastern (MID) AF: 0.00936 AC: 54 AN: 5768

European-Non Finnish (NFE) AF: 0.00150 AC: 1671 AN: 1112010

Other (OTH) AF: 0.00714 AC: 431 AN: 60394

GnomAD4 genome AF: 0.0157 AC: 2398 AN: 152320 Hom.: 75 Cov.: 33 AF XY: 0.0147 AC XY: 1093 AN XY: 74486

African (AFR) AF: 0.0510 AC: 2121 AN: 41560

American (AMR) AF: 0.00555 AC: 85 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.0118 AC: 57 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00150 AC: 102 AN: 68024

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.00568 Hom.: 58

Bravo AF: 0.0174

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00142

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	not provided (5)
-	-	2	Cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
1	-	-	Dilated cardiomyopathy 1C (1)
-	-	1	Dilated cardiomyopathy 1C;C4721886:Myofibrillar myopathy 4 (1)
-	-	1	Myofibrillar myopathy 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0034	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.39
Sift	Benign	0.069	T
Sift4G	Benign	0.60	T
Varity_R		0.23
gMVP		0.19
Mutation Taster		=52/48	polymorphism (auto)

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

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

Other links and lift over

dbSNP: rs34423165;

hg19: chr10-88451715;