10-86706708-C-T

Variant names:

• chr10-86706708-C-T
• rs45459491
• NM_007078.3:c.1074C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_007078.3(LDB3):​c.1074C>T​(p.Ala358Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0377 in 1,611,890 control chromosomes in the GnomAD database, including 1,352 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A358A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.027 (88 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1264 hom.)
• Consequence: LDB3 NM_007078.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:14
• Conservation: PhyloP100: 0.0710
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-86706708-C-T is Benign according to our data. Variant chr10-86706708-C-T is described in ClinVar as Benign. ClinVar VariationId is 36443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.071 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0569 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.1074C>T	p.Ala358Ala	synonymous	Exon 8 of 14	NP_009009.1	O75112-1
	LDB3	NM_001368066.1		c.933C>T	p.Ala311Ala	synonymous	Exon 9 of 15	NP_001354995.1	A0A8I5KV04
	LDB3	NM_001171610.2		c.1101-3197C>T		intron	N/A	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.1074C>T	p.Ala358Ala	synonymous	Exon 8 of 14	ENSP00000355296.3	O75112-1
	LDB3	ENST00000945680.1		c.1278C>T	p.Ala426Ala	synonymous	Exon 8 of 14	ENSP00000615739.1
	LDB3	ENST00000871464.1		c.1074C>T	p.Ala358Ala	synonymous	Exon 8 of 15	ENSP00000541523.1

Frequencies

GnomAD3 genomes AF: 0.0274 AC: 4167 AN: 152166 Hom.: 88 Cov.: 33

Gnomad AFR AF: 0.00654

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0202

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0510

Gnomad FIN AF: 0.0274

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0427

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0327 AC: 7970 AN: 244014 AF XY: 0.0355

Gnomad AFR exome AF: 0.00481

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.000439

Gnomad FIN exome AF: 0.0278

Gnomad NFE exome AF: 0.0443

Gnomad OTH exome AF: 0.0359

GnomAD4 exome AF: 0.0388 AC: 56602 AN: 1459606 Hom.: 1264 Cov.: 32 AF XY: 0.0397 AC XY: 28843 AN XY: 726062

African (AFR) AF: 0.00574 AC: 192 AN: 33442

American (AMR) AF: 0.0129 AC: 577 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 284 AN: 26058

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39660

South Asian (SAS) AF: 0.0582 AC: 5018 AN: 86148

European-Finnish (FIN) AF: 0.0310 AC: 1632 AN: 52608

Middle Eastern (MID) AF: 0.0323 AC: 178 AN: 5508

European-Non Finnish (NFE) AF: 0.0420 AC: 46725 AN: 1111340

Other (OTH) AF: 0.0330 AC: 1987 AN: 60274

GnomAD4 genome AF: 0.0273 AC: 4162 AN: 152284 Hom.: 88 Cov.: 33 AF XY: 0.0274 AC XY: 2037 AN XY: 74468

African (AFR) AF: 0.00652 AC: 271 AN: 41554

American (AMR) AF: 0.0201 AC: 308 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0506 AC: 244 AN: 4818

European-Finnish (FIN) AF: 0.0274 AC: 291 AN: 10622

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0427 AC: 2906 AN: 68012

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.0313 Hom.: 79

Bravo AF: 0.0235

Asia WGS AF: 0.0180 AC: 64 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.9
DANN	Benign	0.47
PhyloP100		0.071
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs45459491; hg19: chr10-88466465; COSMIC: COSV53938805;