rs3740346

Variant names:

• chr10-86692112-G-C
• rs3740346
• NM_007078.3:c.859+47G>C

Your query was ambiguous. Multiple possible variants found:

• chr10-86692112-G-C
• chr10-86692112-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.859+47G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,605,672 control chromosomes in the GnomAD database, including 22,751 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2394 hom., cov: 33)
  • Exomes 𝑓: 0.14 (20357 hom.)
• Consequence: LDB3 NM_007078.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: 0.337
• 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):

• myofibrillar myopathy 4

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• familial dilated cardiomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000289258 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-86692112-G-C is Benign according to our data. Variant chr10-86692112-G-C is described in ClinVar as Benign. ClinVar VariationId is 257338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_007078.3	c.859+47G>C		intron_variant	Intron 6 of 13	ENST00000361373.9	NP_009009.1
LDB3	NM_001368067.1	c.718+47G>C		intron_variant	Intron 7 of 8	ENST00000263066.11	NP_001354996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9	c.859+47G>C		intron_variant	Intron 6 of 13	1	NM_007078.3	ENSP00000355296.3
LDB3	ENST00000263066.11	c.718+47G>C		intron_variant	Intron 7 of 8	1	NM_001368067.1	ENSP00000263066.7
ENSG00000289258	ENST00000443292.2	c.2368+47G>C		intron_variant	Intron 16 of 17	1		ENSP00000393132.2

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21975 AN: 152076 Hom.: 2399 Cov.: 33

Gnomad AFR AF: 0.0881

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.627

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.137

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.139

GnomAD2 exomes AF: 0.192 AC: 46530 AN: 242028 AF XY: 0.186

Gnomad AFR exome AF: 0.0865

Gnomad AMR exome AF: 0.269

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.643

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.123

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.141 AC: 204955 AN: 1453478 Hom.: 20357 Cov.: 30 AF XY: 0.141 AC XY: 101950 AN XY: 723028

African (AFR) AF: 0.0817 AC: 2721 AN: 33316

American (AMR) AF: 0.260 AC: 11477 AN: 44210

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 4167 AN: 26044

East Asian (EAS) AF: 0.619 AC: 24445 AN: 39496

South Asian (SAS) AF: 0.161 AC: 13798 AN: 85766

European-Finnish (FIN) AF: 0.185 AC: 9646 AN: 52080

Middle Eastern (MID) AF: 0.137 AC: 783 AN: 5728

European-Non Finnish (NFE) AF: 0.116 AC: 128310 AN: 1106736

Other (OTH) AF: 0.160 AC: 9608 AN: 60102

GnomAD4 genome AF: 0.144 AC: 21970 AN: 152194 Hom.: 2394 Cov.: 33 AF XY: 0.153 AC XY: 11388 AN XY: 74398

African (AFR) AF: 0.0880 AC: 3658 AN: 41552

American (AMR) AF: 0.200 AC: 3051 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 556 AN: 3472

East Asian (EAS) AF: 0.626 AC: 3231 AN: 5158

South Asian (SAS) AF: 0.185 AC: 894 AN: 4822

European-Finnish (FIN) AF: 0.193 AC: 2046 AN: 10600

Middle Eastern (MID) AF: 0.134 AC: 39 AN: 292

European-Non Finnish (NFE) AF: 0.118 AC: 8045 AN: 67988

Other (OTH) AF: 0.138 AC: 292 AN: 2114

Alfa AF: 0.134 Hom.: 290

Bravo AF: 0.147

Asia WGS AF: 0.355 AC: 1231 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dilated cardiomyopathy 1C Uncertain:1

Aug 19, 2014

Cytogenetics- Mohapatra Lab, Banaras Hindu University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: case-control

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.2
DANN	Benign	0.57
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3740346; hg19: chr10-88451869;