rs45555240

Variant names:

• chr10-86706675-C-A
• rs45555240
• NM_007078.3:c.1041C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-86706675-C-A
• chr10-86706675-C-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.1041C>A​(p.Ser347Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00937 in 1,612,904 control chromosomes in the GnomAD database, including 1,106 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. S347S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.046 (561 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (545 hom.)
• Consequence: LDB3 NM_007078.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: -0.819
• Publications: 6 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=-0.8).
• BP6: Variant 10-86706675-C-A is Benign according to our data. Variant chr10-86706675-C-A is described in ClinVar as Benign. ClinVar VariationId is 36442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.819 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.154 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.1041C>A	p.Ser347Ser	synonymous	Exon 8 of 14	NP_009009.1	O75112-1
	LDB3	NM_001368066.1		c.900C>A	p.Ser300Ser	synonymous	Exon 9 of 15	NP_001354995.1	A0A8I5KV04
	LDB3	NM_001171610.2		c.1101-3230C>A		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.1041C>A	p.Ser347Ser	synonymous	Exon 8 of 14	ENSP00000355296.3	O75112-1
	LDB3	ENST00000945680.1		c.1245C>A	p.Ser415Ser	synonymous	Exon 8 of 14	ENSP00000615739.1
	LDB3	ENST00000871464.1		c.1041C>A	p.Ser347Ser	synonymous	Exon 8 of 15	ENSP00000541523.1

Frequencies

GnomAD3 genomes AF: 0.0462 AC: 7035 AN: 152194 Hom.: 559 Cov.: 33

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0199

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.0344

GnomAD2 exomes AF: 0.0128 AC: 3184 AN: 247946 AF XY: 0.00963

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.00855

Gnomad ASJ exome AF: 0.00433

Gnomad EAS exome AF: 0.00435

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000522

Gnomad OTH exome AF: 0.00694

GnomAD4 exome AF: 0.00552 AC: 8068 AN: 1460592 Hom.: 545 Cov.: 32 AF XY: 0.00492 AC XY: 3574 AN XY: 726632

African (AFR) AF: 0.168 AC: 5625 AN: 33476

American (AMR) AF: 0.0102 AC: 454 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00494 AC: 129 AN: 26100

East Asian (EAS) AF: 0.00479 AC: 190 AN: 39692

South Asian (SAS) AF: 0.00404 AC: 348 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52594

Middle Eastern (MID) AF: 0.0125 AC: 71 AN: 5698

European-Non Finnish (NFE) AF: 0.000389 AC: 433 AN: 1111780

Other (OTH) AF: 0.0136 AC: 818 AN: 60334

GnomAD4 genome AF: 0.0463 AC: 7051 AN: 152312 Hom.: 561 Cov.: 33 AF XY: 0.0443 AC XY: 3298 AN XY: 74494

African (AFR) AF: 0.157 AC: 6542 AN: 41548

American (AMR) AF: 0.0199 AC: 304 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00521 AC: 27 AN: 5186

South Asian (SAS) AF: 0.00559 AC: 27 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 68026

Other (OTH) AF: 0.0341 AC: 72 AN: 2114

Alfa AF: 0.00314 Hom.: 1

Bravo AF: 0.0524

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000890

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	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	-0.80
CADD	Benign	0.23
DANN	Benign	0.67
PhyloP100		-0.82
Mutation Taster		=100/0	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: rs45555240; hg19: chr10-88466432;