10-86681680-C-T

Variant names:

• chr10-86681680-C-T
• rs45487699
• NM_007078.3:c.566C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BS1_Supporting BS2

The NM_007078.3(LDB3):​c.566C>T​(p.Ser189Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000584 in 1,613,396 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S189A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00059 (2 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:10 B:2
• Conservation: PhyloP100: 3.32
• Publications: 21 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3016677).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000519 (79/152358) while in subpopulation AMR AF = 0.000849 (13/15308). AF 95% confidence interval is 0.000547. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• 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.566C>T	p.Ser189Leu	missense	Exon 5 of 14	NP_009009.1	O75112-1
	LDB3	NM_001368067.1	MANE Plus Clinical	c.321+1523C>T		intron	N/A	NP_001354996.1	A0A0S2Z530
	LDB3	NM_001171610.2		c.566C>T	p.Ser189Leu	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.566C>T	p.Ser189Leu	missense	Exon 5 of 14	ENSP00000355296.3	O75112-1
	ENSG00000289258	ENST00000443292.2	TSL:1	c.2075C>T	p.Ser692Leu	missense	Exon 15 of 18	ENSP00000393132.2	C9JWU6
	LDB3	ENST00000372056.8	TSL:1	c.566C>T	p.Ser189Leu	missense	Exon 4 of 8	ENSP00000361126.4	O75112-4

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152240 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000649 AC: 162 AN: 249768 AF XY: 0.000679

Gnomad AFR exome AF: 0.0000628

Gnomad AMR exome AF: 0.000753

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000973

Gnomad NFE exome AF: 0.000735

Gnomad OTH exome AF: 0.000823

GnomAD4 exome AF: 0.000591 AC: 863 AN: 1461038 Hom.: 2 Cov.: 32 AF XY: 0.000594 AC XY: 432 AN XY: 726808

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.000671 AC: 30 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.000765 AC: 66 AN: 86226

European-Finnish (FIN) AF: 0.00112 AC: 59 AN: 52788

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000602 AC: 669 AN: 1111882

Other (OTH) AF: 0.000580 AC: 35 AN: 60370

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152358 Hom.: 0 Cov.: 34 AF XY: 0.000537 AC XY: 40 AN XY: 74508

African (AFR) AF: 0.000144 AC: 6 AN: 41590

American (AMR) AF: 0.000849 AC: 13 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000677 Hom.: 0

Bravo AF: 0.000529

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000560 AC: 68

EpiCase AF: 0.000872

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	not provided (5)
-	2	-	not specified (2)
-	1	-	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1A (1)
1	-	-	Dilated cardiomyopathy 1C (1)
-	1	-	Dilated cardiomyopathy 1C;C4721886:Myofibrillar myopathy 4 (1)
1	-	-	Familial hypertrophic cardiomyopathy 24 (1)
-	1	-	Myofibrillar myopathy 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.3
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.18
Sift	Benign	0.68	T
Sift4G	Benign	0.72	T
Polyphen		0.0020	B
Vest4		0.72
MVP		0.74
MPC		0.18
ClinPred		0.032	T
GERP RS		3.8
Varity_R		0.064
gMVP		0.77
Mutation Taster		=10/90	disease causing (ClinVar)

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: rs45487699; hg19: chr10-88441437; COSMIC: COSV53943114;