rs144445130

Variant names:

• chr10-86699293-G-A
• rs144445130
• NM_001368067.1:c.771G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-86699293-G-A
• chr10-86699293-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001368067.1(LDB3):​c.771G>A​(p.Thr257Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000638 in 1,611,962 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (4 hom.)
• Consequence: LDB3 NM_001368067.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 3.33
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 10-86699293-G-A is Benign according to our data. Variant chr10-86699293-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43884.
• BP7: Synonymous conserved (PhyloP=3.33 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000516 (78/151292) while in subpopulation SAS AF = 0.00398 (19/4774). AF 95% confidence interval is 0.00261. There are 0 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001368067.1. 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_001368067.1	MANE Plus Clinical	c.771G>A	p.Thr257Thr	synonymous	Exon 9 of 9	NP_001354996.1	A0A0S2Z530
	LDB3	NM_007078.3	MANE Select	c.896+6722G>A		intron	N/A	NP_009009.1	O75112-1
	LDB3	NM_001171611.2		c.1116G>A	p.Thr372Thr	synonymous	Exon 9 of 9	NP_001165082.1	O75112-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB3	ENST00000263066.11	TSL:1 MANE Plus Clinical	c.771G>A	p.Thr257Thr	synonymous	Exon 9 of 9	ENSP00000263066.7	O75112-6
	ENSG00000289258	ENST00000443292.2	TSL:1	c.2421G>A	p.Thr807Thr	synonymous	Exon 18 of 18	ENSP00000393132.2	C9JWU6
	LDB3	ENST00000372056.8	TSL:1	c.1116G>A	p.Thr372Thr	synonymous	Exon 8 of 8	ENSP00000361126.4	O75112-4

Frequencies

GnomAD3 genomes AF: 0.000516 AC: 78 AN: 151174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000487

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000790

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00398

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000545

Gnomad OTH AF: 0.000483

GnomAD2 exomes AF: 0.000913 AC: 227 AN: 248618 AF XY: 0.00106

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.000596

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.000651 AC: 951 AN: 1460670 Hom.: 4 Cov.: 35 AF XY: 0.000756 AC XY: 549 AN XY: 726634

African (AFR) AF: 0.0000299 AC: 1 AN: 33462

American (AMR) AF: 0.00105 AC: 47 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00299 AC: 78 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00339 AC: 292 AN: 86240

European-Finnish (FIN) AF: 0.0000751 AC: 4 AN: 53246

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5764

European-Non Finnish (NFE) AF: 0.000421 AC: 468 AN: 1111202

Other (OTH) AF: 0.000846 AC: 51 AN: 60316

GnomAD4 genome AF: 0.000516 AC: 78 AN: 151292 Hom.: 0 Cov.: 32 AF XY: 0.000623 AC XY: 46 AN XY: 73828

African (AFR) AF: 0.0000486 AC: 2 AN: 41190

American (AMR) AF: 0.000789 AC: 12 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.00398 AC: 19 AN: 4774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10370

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

European-Non Finnish (NFE) AF: 0.000545 AC: 37 AN: 67864

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000723 Hom.: 0

Bravo AF: 0.000604

EpiCase AF: 0.000763

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	-	3	not specified (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Myofibrillar myopathy 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Benign	0.75
PhyloP100		3.3
Mutation Taster		=88/12	polymorphism

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: rs144445130; hg19: chr10-88459050; COSMIC: COSV53938303;