rs35507268

Variant names:

• chr10-86681466-G-A
• rs35507268
• NM_007078.3:c.352G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007078.3(LDB3):​c.352G>A​(p.Val118Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00594 in 1,606,432 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0061 (32 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 0.0900
• Publications: 15 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 (MetaRNN=0.005024433).
• BP6: Variant 10-86681466-G-A is Benign according to our data. Variant chr10-86681466-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00394 (601/152364) while in subpopulation NFE AF = 0.00591 (402/68034). AF 95% confidence interval is 0.00543. There are 2 homozygotes in GnomAd4. There are 296 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.352G>A	p.Val118Met	missense	Exon 5 of 14	NP_009009.1	O75112-1
	LDB3	NM_001368067.1	MANE Plus Clinical	c.321+1309G>A		intron	N/A	NP_001354996.1	A0A0S2Z530
	LDB3	NM_001171610.2		c.352G>A	p.Val118Met	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.352G>A	p.Val118Met	missense	Exon 5 of 14	ENSP00000355296.3	O75112-1
	ENSG00000289258	ENST00000443292.2	TSL:1	c.1861G>A	p.Val621Met	missense	Exon 15 of 18	ENSP00000393132.2	C9JWU6
	LDB3	ENST00000372056.8	TSL:1	c.352G>A	p.Val118Met	missense	Exon 4 of 8	ENSP00000361126.4	O75112-4

Frequencies

GnomAD3 genomes AF: 0.00395 AC: 601 AN: 152246 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00414

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00591

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00432 AC: 1042 AN: 241370 AF XY: 0.00434

Gnomad AFR exome AF: 0.000959

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00593

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00501

Gnomad NFE exome AF: 0.00685

Gnomad OTH exome AF: 0.00416

GnomAD4 exome AF: 0.00614 AC: 8934 AN: 1454068 Hom.: 32 Cov.: 32 AF XY: 0.00605 AC XY: 4377 AN XY: 723726

African (AFR) AF: 0.000747 AC: 25 AN: 33456

American (AMR) AF: 0.00186 AC: 83 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00613 AC: 160 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000916 AC: 79 AN: 86232

European-Finnish (FIN) AF: 0.00514 AC: 237 AN: 46120

Middle Eastern (MID) AF: 0.000355 AC: 2 AN: 5640

European-Non Finnish (NFE) AF: 0.00728 AC: 8095 AN: 1111780

Other (OTH) AF: 0.00419 AC: 253 AN: 60324

GnomAD4 genome AF: 0.00394 AC: 601 AN: 152364 Hom.: 2 Cov.: 34 AF XY: 0.00397 AC XY: 296 AN XY: 74514

African (AFR) AF: 0.00108 AC: 45 AN: 41592

American (AMR) AF: 0.00509 AC: 78 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

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

European-Finnish (FIN) AF: 0.00414 AC: 44 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00591 AC: 402 AN: 68034

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00581 Hom.: 6

Bravo AF: 0.00363

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.00458 AC: 553

EpiCase AF: 0.00534

EpiControl AF: 0.00593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	6	not provided (6)
-	-	2	Cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1C;C4721886:Myofibrillar myopathy 4 (1)
-	-	1	LDB3-related disorder (1)
-	-	1	Myofibrillar myopathy 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.073	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.090
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.022
Sift	Benign	0.17	T
Sift4G	Benign	0.22	T
Polyphen		0.0010	B
Vest4		0.22
MVP		0.62
MPC		0.20
ClinPred		0.0053	T
GERP RS		0.30
Varity_R		0.039
gMVP		0.26
Mutation Taster		=98/2	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: rs35507268; hg19: chr10-88441223;