NM_007078.3:c.1653C>T

Variant names:

• chr10-86716748-C-T
• rs45581435
• NM_007078.3:c.1653C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_007078.3(LDB3):​c.1653C>T​(p.Cys551Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000567 in 1,611,646 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00091 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00053 (5 hom.)
• Consequence: LDB3 NM_007078.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.163
• Publications: 2 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 10-86716748-C-T is Benign according to our data. Variant chr10-86716748-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.163 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000913 (139/152318) while in subpopulation NFE AF = 0.00173 (118/68026). AF 95% confidence interval is 0.00148. There are 1 homozygotes in GnomAd4. There are 75 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.1653C>T	p.Cys551Cys	synonymous	Exon 10 of 14	NP_009009.1	O75112-1
	LDB3	NM_001171610.2		c.1668C>T	p.Cys556Cys	synonymous	Exon 10 of 14	NP_001165081.1	O75112-7
	LDB3	NM_001368066.1		c.1512C>T	p.Cys504Cys	synonymous	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.1653C>T	p.Cys551Cys	synonymous	Exon 10 of 14	ENSP00000355296.3	O75112-1
	LDB3	ENST00000945680.1		c.1857C>T	p.Cys619Cys	synonymous	Exon 10 of 14	ENSP00000615739.1
	LDB3	ENST00000871464.1		c.1794C>T	p.Cys598Cys	synonymous	Exon 11 of 15	ENSP00000541523.1

Frequencies

GnomAD3 genomes AF: 0.000907 AC: 138 AN: 152200 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000516 AC: 126 AN: 244162 AF XY: 0.000460

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000883

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0000553

Gnomad FIN exome AF: 0.000668

Gnomad NFE exome AF: 0.000932

Gnomad OTH exome AF: 0.000837

GnomAD4 exome AF: 0.000530 AC: 774 AN: 1459328 Hom.: 5 Cov.: 36 AF XY: 0.000543 AC XY: 394 AN XY: 725876

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.000158 AC: 7 AN: 44394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39618

South Asian (SAS) AF: 0.000128 AC: 11 AN: 85974

European-Finnish (FIN) AF: 0.000912 AC: 48 AN: 52610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.000607 AC: 674 AN: 1111206

Other (OTH) AF: 0.000547 AC: 33 AN: 60294

GnomAD4 genome AF: 0.000913 AC: 139 AN: 152318 Hom.: 1 Cov.: 31 AF XY: 0.00101 AC XY: 75 AN XY: 74476

African (AFR) AF: 0.0000962 AC: 4 AN: 41564

American (AMR) AF: 0.000131 AC: 2 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00173 AC: 118 AN: 68026

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00113 Hom.: 3

Bravo AF: 0.000408

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	LDB3-related disorder (1)
-	-	1	Myofibrillar myopathy 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	8.0
DANN	Benign	0.60
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs45581435; hg19: chr10-88476505; COSMIC: COSV53947164; COSMIC: COSV53947164;