rs45539535

Variant names:

• chr10-86709930-G-A
• rs45539535
• NM_007078.3:c.1111G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_007078.3(LDB3):​c.1111G>A​(p.Ala371Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000919 in 1,611,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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 0.00053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00096 (0 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 0.133
• Publications: 4 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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014563024).
• BP6: Variant 10-86709930-G-A is Benign according to our data. Variant chr10-86709930-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45511.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000532 (81/152240) while in subpopulation NFE AF = 0.000926 (63/68004). AF 95% confidence interval is 0.000742. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.1111G>A	p.Ala371Thr	missense	Exon 9 of 14	NP_009009.1	O75112-1
	LDB3	NM_001171610.2		c.1126G>A	p.Ala376Thr	missense	Exon 9 of 14	NP_001165081.1	O75112-7
	LDB3	NM_001368066.1		c.970G>A	p.Ala324Thr	missense	Exon 10 of 15	NP_001354995.1	A0A8I5KV04

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB3	ENST00000361373.9	TSL:1 MANE Select	c.1111G>A	p.Ala371Thr	missense	Exon 9 of 14	ENSP00000355296.3	O75112-1
	LDB3	ENST00000945680.1		c.1315G>A	p.Ala439Thr	missense	Exon 9 of 14	ENSP00000615739.1
	LDB3	ENST00000871464.1		c.1111G>A	p.Ala371Thr	missense	Exon 9 of 15	ENSP00000541523.1

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152122 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000602 AC: 149 AN: 247472 AF XY: 0.000557

Gnomad AFR exome AF: 0.000316

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000246

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.000823

GnomAD4 exome AF: 0.000959 AC: 1400 AN: 1459658 Hom.: 0 Cov.: 33 AF XY: 0.000907 AC XY: 659 AN XY: 726240

African (AFR) AF: 0.000179 AC: 6 AN: 33476

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.000272 AC: 14 AN: 51384

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5698

European-Non Finnish (NFE) AF: 0.00118 AC: 1316 AN: 1111944

Other (OTH) AF: 0.000679 AC: 41 AN: 60352

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.000511 AC XY: 38 AN XY: 74436

African (AFR) AF: 0.000193 AC: 8 AN: 41552

American (AMR) AF: 0.000458 AC: 7 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000926 AC: 63 AN: 68004

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.000529

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000635 AC: 77

EpiCase AF: 0.00115

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	3	not specified (3)
-	1	-	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	LDB3-related disorder (1)
-	-	1	Myofibrillar myopathy 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	9.8
DANN	Benign	0.57
DEOGEN2	Benign	0.27	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.13
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.086
Sift	Benign	0.049	D
Sift4G	Benign	0.13	T
Polyphen		0.0010	B
Vest4		0.24
MVP		0.81
MPC		0.19
ClinPred		0.0027	T
GERP RS		-0.033
Varity_R		0.036
gMVP		0.40
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs45539535; hg19: chr10-88469687; COSMIC: COSV107309334;