10-86710080-C-G

Variant names:

• chr10-86710080-C-G
• rs11597201
• NM_007078.3:c.1231+30C>G

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.1231+30C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0359 in 1,608,826 control chromosomes in the GnomAD database, including 1,286 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (298 hom., cov: 33)
  • Exomes 𝑓: 0.034 (988 hom.)
• Consequence: LDB3 NM_007078.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.212
• 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):

• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 10-86710080-C-G is Benign according to our data. Variant chr10-86710080-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_007078.3	c.1231+30C>G		intron_variant	Intron 9 of 13	ENST00000361373.9	NP_009009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9	c.1231+30C>G		intron_variant	Intron 9 of 13	1	NM_007078.3	ENSP00000355296.3

Frequencies

GnomAD3 genomes AF: 0.0510 AC: 7761 AN: 152106 Hom.: 295 Cov.: 33

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.0228

Gnomad ASJ AF: 0.0637

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.0209

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0352

Gnomad OTH AF: 0.0407

GnomAD2 exomes AF: 0.0328 AC: 7748 AN: 236054 AF XY: 0.0322

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.0190

Gnomad ASJ exome AF: 0.0643

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.0181

Gnomad NFE exome AF: 0.0339

Gnomad OTH exome AF: 0.0371

GnomAD4 exome AF: 0.0343 AC: 49908 AN: 1456602 Hom.: 988 Cov.: 33 AF XY: 0.0342 AC XY: 24761 AN XY: 724604

African (AFR) AF: 0.103 AC: 3454 AN: 33432

American (AMR) AF: 0.0195 AC: 865 AN: 44428

Ashkenazi Jewish (ASJ) AF: 0.0596 AC: 1552 AN: 26048

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39620

South Asian (SAS) AF: 0.0292 AC: 2508 AN: 85920

European-Finnish (FIN) AF: 0.0208 AC: 1043 AN: 50150

Middle Eastern (MID) AF: 0.0681 AC: 391 AN: 5744

European-Non Finnish (NFE) AF: 0.0339 AC: 37699 AN: 1111106

Other (OTH) AF: 0.0397 AC: 2390 AN: 60154

GnomAD4 genome AF: 0.0511 AC: 7784 AN: 152224 Hom.: 298 Cov.: 33 AF XY: 0.0482 AC XY: 3588 AN XY: 74432

African (AFR) AF: 0.105 AC: 4343 AN: 41542

American (AMR) AF: 0.0227 AC: 347 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0637 AC: 221 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.0239 AC: 115 AN: 4818

European-Finnish (FIN) AF: 0.0209 AC: 222 AN: 10608

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0352 AC: 2395 AN: 68000

Other (OTH) AF: 0.0460 AC: 97 AN: 2110

Alfa AF: 0.0265 Hom.: 20

Bravo AF: 0.0534

Asia WGS AF: 0.0290 AC: 101 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.2
DANN	Benign	0.68
PhyloP100		-0.21
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: rs11597201; hg19: chr10-88469837;