rs3740343

Variant names:

• chr10-86679436-G-A
• rs3740343
• NM_007078.3:c.163G>A

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.163G>A​(p.Val55Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00233 in 1,614,106 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (14 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (113 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 3.58
• Publications: 18 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=0.0027198195).
• BP6: Variant 10-86679436-G-A is Benign according to our data. Variant chr10-86679436-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0727 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.163G>A	p.Val55Ile	missense	Exon 3 of 14	NP_009009.1	O75112-1
	LDB3	NM_001368067.1	MANE Plus Clinical	c.163G>A	p.Val55Ile	missense	Exon 3 of 9	NP_001354996.1	A0A0S2Z530
	LDB3	NM_001171610.2		c.163G>A	p.Val55Ile	missense	Exon 3 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.163G>A	p.Val55Ile	missense	Exon 3 of 14	ENSP00000355296.3	O75112-1
	LDB3	ENST00000263066.11	TSL:1 MANE Plus Clinical	c.163G>A	p.Val55Ile	missense	Exon 3 of 9	ENSP00000263066.7	O75112-6
	ENSG00000289258	ENST00000443292.2	TSL:1	c.1672G>A	p.Val558Ile	missense	Exon 13 of 18	ENSP00000393132.2	C9JWU6

Frequencies

GnomAD3 genomes AF: 0.00383 AC: 583 AN: 152146 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.0790

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00782 AC: 1967 AN: 251402 AF XY: 0.00729

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.00538

Gnomad ASJ exome AF: 0.00605

Gnomad EAS exome AF: 0.0869

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00217 AC: 3179 AN: 1461842 Hom.: 113 Cov.: 32 AF XY: 0.00214 AC XY: 1553 AN XY: 727228

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.00510 AC: 228 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00532 AC: 139 AN: 26136

East Asian (EAS) AF: 0.0569 AC: 2257 AN: 39700

South Asian (SAS) AF: 0.00157 AC: 135 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000953 AC: 106 AN: 1112002

Other (OTH) AF: 0.00485 AC: 293 AN: 60396

GnomAD4 genome AF: 0.00383 AC: 583 AN: 152264 Hom.: 14 Cov.: 33 AF XY: 0.00411 AC XY: 306 AN XY: 74450

African (AFR) AF: 0.000770 AC: 32 AN: 41546

American (AMR) AF: 0.00536 AC: 82 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.0790 AC: 410 AN: 5188

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68020

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00178 Hom.: 20

Bravo AF: 0.00515

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00723 AC: 878

Asia WGS AF: 0.0270 AC: 95 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	2	Myofibrillar myopathy 4 (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1C (1)
-	-	1	Dilated cardiomyopathy 1C;C4721886:Myofibrillar myopathy 4 (1)
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Myofibrillar Myopathy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.047
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.31	N
PhyloP100		3.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.042
Sift	Benign	0.95	T
Sift4G	Benign	1.0	T
Polyphen		0.44	B
Vest4		0.69
MVP		0.48
MPC		0.18
ClinPred		0.013	T
GERP RS		3.8
Varity_R		0.11
gMVP		0.21
Mutation Taster		=93/7	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

Other links and lift over

dbSNP: rs3740343; hg19: chr10-88439193; COSMIC: COSV53952330;