NM_007078.3:c.689+3825G>C

Variant names:

• chr10-86685628-G-C
• rs3740345
• NM_007078.3:c.689+3825G>C

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.689+3825G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.719 in 1,606,888 control chromosomes in the GnomAD database, including 419,785 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34777 hom., cov: 32)
  • Exomes 𝑓: 0.72 (385008 hom.)
• Consequence: LDB3 NM_007078.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: -0.492
• Publications: 10 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 (BayesDel_noAF=-0.92).
• BP6: Variant 10-86685628-G-C is Benign according to our data. Variant chr10-86685628-G-C is described in ClinVar as Benign. ClinVar VariationId is 257337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.767 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.689+3825G>C		intron	N/A	NP_009009.1	O75112-1
	LDB3	NM_001368067.1	MANE Plus Clinical	c.322-50G>C		intron	N/A	NP_001354996.1	A0A0S2Z530
	LDB3	NM_001171610.2		c.690-1441G>C		intron	N/A	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.689+3825G>C		intron	N/A	ENSP00000355296.3	O75112-1
	LDB3	ENST00000263066.11	TSL:1 MANE Plus Clinical	c.322-50G>C		intron	N/A	ENSP00000263066.7	O75112-6
	ENSG00000289258	ENST00000443292.2	TSL:1	c.2198+3825G>C		intron	N/A	ENSP00000393132.2	C9JWU6

Frequencies

GnomAD3 genomes AF: 0.670 AC: 101848 AN: 151916 Hom.: 34770 Cov.: 32

Gnomad AFR AF: 0.588

Gnomad AMI AF: 0.757

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.749

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.787

Gnomad FIN AF: 0.641

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.747

Gnomad OTH AF: 0.679

GnomAD2 exomes AF: 0.675 AC: 168369 AN: 249358 AF XY: 0.692

Gnomad AFR exome AF: 0.592

Gnomad AMR exome AF: 0.486

Gnomad ASJ exome AF: 0.747

Gnomad EAS exome AF: 0.457

Gnomad FIN exome AF: 0.647

Gnomad NFE exome AF: 0.744

Gnomad OTH exome AF: 0.695

GnomAD4 exome AF: 0.724 AC: 1052756 AN: 1454854 Hom.: 385008 Cov.: 30 AF XY: 0.727 AC XY: 526907 AN XY: 724346

African (AFR) AF: 0.587 AC: 19553 AN: 33316

American (AMR) AF: 0.496 AC: 22193 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.746 AC: 19473 AN: 26096

East Asian (EAS) AF: 0.462 AC: 18297 AN: 39646

South Asian (SAS) AF: 0.793 AC: 68294 AN: 86124

European-Finnish (FIN) AF: 0.656 AC: 34887 AN: 53204

Middle Eastern (MID) AF: 0.767 AC: 4414 AN: 5758

European-Non Finnish (NFE) AF: 0.744 AC: 822978 AN: 1105850

Other (OTH) AF: 0.709 AC: 42667 AN: 60150

GnomAD4 genome AF: 0.670 AC: 101887 AN: 152034 Hom.: 34777 Cov.: 32 AF XY: 0.665 AC XY: 49389 AN XY: 74298

African (AFR) AF: 0.588 AC: 24356 AN: 41434

American (AMR) AF: 0.575 AC: 8794 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.749 AC: 2596 AN: 3468

East Asian (EAS) AF: 0.470 AC: 2425 AN: 5156

South Asian (SAS) AF: 0.788 AC: 3800 AN: 4820

European-Finnish (FIN) AF: 0.641 AC: 6783 AN: 10576

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.747 AC: 50811 AN: 67988

Other (OTH) AF: 0.673 AC: 1418 AN: 2108

Alfa AF: 0.719 Hom.: 7283

Bravo AF: 0.655

Asia WGS AF: 0.617 AC: 2145 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Dilated cardiomyopathy 1C (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.1
DANN	Benign	0.55
PhyloP100		-0.49
Mutation Taster		=100/0	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: rs3740345; hg19: chr10-88445385; COSMIC: COSV53940602;