NM_007078.3:c.1330G>C

Variant names:

• chr10-86716425-G-C
• rs786205350
• NM_007078.3:c.1330G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_007078.3(LDB3):​c.1330G>C​(p.Ala444Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A444T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0074 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000065 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.985
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13430336).

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.1330G>C	p.Ala444Pro	missense	Exon 10 of 14	NP_009009.1	O75112-1
	LDB3	NM_001171610.2		c.1345G>C	p.Ala449Pro	missense	Exon 10 of 14	NP_001165081.1	O75112-7
	LDB3	NM_001368066.1		c.1189G>C	p.Ala397Pro	missense	Exon 11 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.1330G>C	p.Ala444Pro	missense	Exon 10 of 14	ENSP00000355296.3	O75112-1
	LDB3	ENST00000945680.1		c.1534G>C	p.Ala512Pro	missense	Exon 10 of 14	ENSP00000615739.1
	LDB3	ENST00000871464.1		c.1471G>C	p.Ala491Pro	missense	Exon 11 of 15	ENSP00000541523.1

Frequencies

GnomAD3 genomes AF: 0.00738 AC: 151 AN: 20470 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.00389

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.0227

Gnomad NFE AF: 0.00420

Gnomad OTH AF: 0.0138

GnomAD2 exomes AF: 0.000116 AC: 11 AN: 95094 AF XY: 0.0000572

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000210

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0000814

Gnomad NFE exome AF: 0.0000473

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000645 AC: 6 AN: 929566 Hom.: 0 Cov.: 35 AF XY: 0.00000658 AC XY: 3 AN XY: 455818

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000507 AC: 1 AN: 19718

American (AMR) AF: 0.00 AC: 0 AN: 24578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12854

East Asian (EAS) AF: 0.00 AC: 0 AN: 9762

South Asian (SAS) AF: 0.0000189 AC: 1 AN: 52948

European-Finnish (FIN) AF: 0.0000845 AC: 2 AN: 23658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2140

European-Non Finnish (NFE) AF: 0.00000266 AC: 2 AN: 751090

Other (OTH) AF: 0.00 AC: 0 AN: 32818

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00737 AC: 151 AN: 20500 Hom.: 0 Cov.: 0 AF XY: 0.00829 AC XY: 85 AN XY: 10250

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0108 AC: 57 AN: 5262

American (AMR) AF: 0.0157 AC: 26 AN: 1656

Ashkenazi Jewish (ASJ) AF: 0.00389 AC: 2 AN: 514

East Asian (EAS) AF: 0.00 AC: 0 AN: 566

South Asian (SAS) AF: 0.00 AC: 0 AN: 618

European-Finnish (FIN) AF: 0.0183 AC: 17 AN: 930

Middle Eastern (MID) AF: 0.0238 AC: 1 AN: 42

European-Non Finnish (NFE) AF: 0.00420 AC: 44 AN: 10472

Other (OTH) AF: 0.0134 AC: 4 AN: 298

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.98
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.017
Sift	Uncertain	0.024	D
Sift4G	Benign	0.13	T
Polyphen		0.96	D
Vest4		0.20
MutPred		0.31		Gain of glycosylation at A444 (P = 0.004)
MVP		0.68
MPC		0.34
ClinPred		0.030	T
GERP RS		2.0
Varity_R		0.068
gMVP		0.26
Mutation Taster		=87/13	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: rs786205350; hg19: chr10-88476182; COSMIC: COSV53940056; COSMIC: COSV53940056;