rs45618633

Variant names:

• chr10-86718772-G-A
• rs45618633
• NM_007078.3:c.1903G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-86718772-G-A
• chr10-86718772-G-C
• chr10-86718772-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007078.3(LDB3):​c.1903G>A​(p.Val635Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00433 in 1,614,098 control chromosomes in the GnomAD database, including 187 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V635G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.019 (79 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (108 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 2.47
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009906501).
• BP6: Variant 10-86718772-G-A is Benign according to our data. Variant chr10-86718772-G-A is described in ClinVar as Benign. ClinVar VariationId is 36445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0627 is higher than 0.05.

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.1903G>A	p.Val635Ile	missense	Exon 12 of 14	NP_009009.1	O75112-1
	LDB3	NM_001171610.2		c.1918G>A	p.Val640Ile	missense	Exon 12 of 14	NP_001165081.1	O75112-7
	LDB3	NM_001368066.1		c.1762G>A	p.Val588Ile	missense	Exon 13 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.1903G>A	p.Val635Ile	missense	Exon 12 of 14	ENSP00000355296.3	O75112-1
	LDB3	ENST00000477489.1	TSL:1	c.43G>A	p.Val15Ile	missense	Exon 1 of 2	ENSP00000485538.1	A0A096LPD7
	LDB3	ENST00000945680.1		c.2107G>A	p.Val703Ile	missense	Exon 12 of 14	ENSP00000615739.1

Frequencies

GnomAD3 genomes AF: 0.0193 AC: 2943 AN: 152096 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.0647

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00521

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00602 AC: 1514 AN: 251446 AF XY: 0.00484

Gnomad AFR exome AF: 0.0634

Gnomad AMR exome AF: 0.00437

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.00435

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000545

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00276 AC: 4030 AN: 1461884 Hom.: 108 Cov.: 32 AF XY: 0.00265 AC XY: 1929 AN XY: 727240

African (AFR) AF: 0.0679 AC: 2272 AN: 33480

American (AMR) AF: 0.00467 AC: 209 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00494 AC: 129 AN: 26136

East Asian (EAS) AF: 0.00479 AC: 190 AN: 39700

South Asian (SAS) AF: 0.00363 AC: 313 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00919 AC: 53 AN: 5768

European-Non Finnish (NFE) AF: 0.000396 AC: 440 AN: 1112010

Other (OTH) AF: 0.00702 AC: 424 AN: 60396

GnomAD4 genome AF: 0.0194 AC: 2952 AN: 152214 Hom.: 79 Cov.: 32 AF XY: 0.0189 AC XY: 1407 AN XY: 74414

African (AFR) AF: 0.0647 AC: 2688 AN: 41520

American (AMR) AF: 0.00739 AC: 113 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 14 AN: 3468

East Asian (EAS) AF: 0.00522 AC: 27 AN: 5170

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4820

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68014

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.00648 Hom.: 46

Bravo AF: 0.0211

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0635 AC: 280

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00698 AC: 848

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Cardiomyopathy (2)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Myofibrillar myopathy 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.5
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.17
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.037	D
Polyphen		0.80	P
Vest4		0.30
MVP		0.85
MPC		0.16
ClinPred		0.011	T
GERP RS		3.6
PromoterAI		-0.024	Neutral
Varity_R		0.11
gMVP		0.14
Mutation Taster		=95/5	polymorphism (auto)

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: rs45618633; hg19: chr10-88478529; COSMIC: COSV108798140;