rs121908338

Variant names:

• chr10-86687073-G-A
• rs121908338
• NM_001368067.1:c.349G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-86687073-G-A
• chr10-86687073-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001368067.1(LDB3):​c.349G>A​(p.Asp117Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00376 in 1,613,780 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 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. D117H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0071 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (31 hom.)
• Consequence: LDB3 NM_001368067.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:19
• Conservation: PhyloP100: 6.87
• Publications: 29 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018208385).
• BP6: Variant 10-86687073-G-A is Benign according to our data. Variant chr10-86687073-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 4733.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00708 (1077/152102) while in subpopulation AFR AF = 0.0149 (620/41494). AF 95% confidence interval is 0.014. There are 8 homozygotes in GnomAd4. There are 517 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.349G>A	p.Asp117Asn	missense	Exon 6 of 9	NP_001354996.1	A0A0S2Z530
	LDB3	NM_007078.3	MANE Select	c.690-4823G>A		intron	N/A	NP_009009.1	O75112-1
	LDB3	NM_001171610.2		c.694G>A	p.Asp232Asn	missense	Exon 6 of 14	NP_001165081.1	O75112-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB3	ENST00000263066.11	TSL:1 MANE Plus Clinical	c.349G>A	p.Asp117Asn	missense	Exon 6 of 9	ENSP00000263066.7	O75112-6
	LDB3	ENST00000372056.8	TSL:1	c.694G>A	p.Asp232Asn	missense	Exon 5 of 8	ENSP00000361126.4	O75112-4
	LDB3	ENST00000372066.8	TSL:1	c.349G>A	p.Asp117Asn	missense	Exon 5 of 8	ENSP00000361136.3	O75112-6

Frequencies

GnomAD3 genomes AF: 0.00710 AC: 1079 AN: 151984 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00879

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00333

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00450 AC: 1122 AN: 249184 AF XY: 0.00457

Gnomad AFR exome AF: 0.0157

Gnomad AMR exome AF: 0.00542

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00404

Gnomad OTH exome AF: 0.00876

GnomAD4 exome AF: 0.00342 AC: 4996 AN: 1461678 Hom.: 31 Cov.: 33 AF XY: 0.00356 AC XY: 2586 AN XY: 727106

African (AFR) AF: 0.0170 AC: 568 AN: 33480

American (AMR) AF: 0.00608 AC: 272 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 264 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00255 AC: 220 AN: 86248

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53396

Middle Eastern (MID) AF: 0.0354 AC: 203 AN: 5740

European-Non Finnish (NFE) AF: 0.00278 AC: 3091 AN: 1111878

Other (OTH) AF: 0.00613 AC: 370 AN: 60380

GnomAD4 genome AF: 0.00708 AC: 1077 AN: 152102 Hom.: 8 Cov.: 33 AF XY: 0.00695 AC XY: 517 AN XY: 74350

African (AFR) AF: 0.0149 AC: 620 AN: 41494

American (AMR) AF: 0.00878 AC: 134 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00334 AC: 16 AN: 4794

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10586

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.00321 AC: 218 AN: 68008

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.00503 Hom.: 11

Bravo AF: 0.00821

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.0125 AC: 51

ESP6500EA AF: 0.00397 AC: 33

ExAC AF: 0.00454 AC: 549

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00567

EpiControl AF: 0.00729

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	7	not specified (7)
-	2	-	Dilated cardiomyopathy 1C (2)
-	-	2	Myofibrillar myopathy 4 (2)
-	-	2	Primary dilated cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Benign	-0.14
Eigen_PC	Benign	0.058
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.54	T
PhyloP100		6.9
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.27
Sift	Uncertain	0.018	D
Sift4G	Benign	0.41	T
Polyphen		0.0040	B
Vest4		0.46
MVP		0.78
MPC		0.26
ClinPred		0.027	T
GERP RS		4.1
gMVP		0.55
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121908338; hg19: chr10-88446830; COSMIC: COSV53941502;