10-86699239-TTCTCTCTCTCTCTCTCTCTC-TTCTCTCTCTCTC

Variant names:

• chr10-86699239-TTCTCTCTC-T
• rs71019410
• NM_007078.3:c.896+6690_896+6697delCTCTCTCT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_007078.3(LDB3):​c.896+6690_896+6697delCTCTCTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,527,406 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 0)
  • Exomes 𝑓: 0.023 (0 hom.)
• Consequence: LDB3 NM_007078.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.30
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 10-86699239-TTCTCTCTC-T is Benign according to our data. Variant chr10-86699239-TTCTCTCTC-T is described in ClinVar as Benign. ClinVar VariationId is 1294149.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000908 (135/148620) while in subpopulation AFR AF = 0.00213 (86/40426). AF 95% confidence interval is 0.00176. There are 0 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB3	NM_007078.3	MANE Select	c.896+6690_896+6697delCTCTCTCT		intron	N/A	NP_009009.1
	LDB3	NM_001368067.1	MANE Plus Clinical	c.756-17_756-10delCTCTCTCT		intron	N/A	NP_001354996.1
	LDB3	NM_001171610.2		c.1100+6690_1100+6697delCTCTCTCT		intron	N/A	NP_001165081.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB3	ENST00000361373.9	TSL:1 MANE Select	c.896+6669_896+6676delTCTCTCTC		intron	N/A	ENSP00000355296.3
	LDB3	ENST00000263066.11	TSL:1 MANE Plus Clinical	c.756-38_756-31delTCTCTCTC		intron	N/A	ENSP00000263066.7
	ENSG00000289258	ENST00000443292.2	TSL:1	c.2406-38_2406-31delTCTCTCTC		intron	N/A	ENSP00000393132.2

Frequencies

GnomAD3 genomes AF: 0.000875 AC: 130 AN: 148522 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00206

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00121

Gnomad ASJ AF: 0.000291

Gnomad EAS AF: 0.000199

Gnomad SAS AF: 0.000435

Gnomad FIN AF: 0.00119

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000179

Gnomad OTH AF: 0.000492

GnomAD2 exomes AF: 0.0450 AC: 10149 AN: 225518 AF XY: 0.0415

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.0556

Gnomad ASJ exome AF: 0.0281

Gnomad EAS exome AF: 0.171

Gnomad FIN exome AF: 0.0209

Gnomad NFE exome AF: 0.0220

Gnomad OTH exome AF: 0.0294

GnomAD4 exome AF: 0.0227 AC: 31362 AN: 1378786 Hom.: 0 AF XY: 0.0226 AC XY: 15585 AN XY: 688562

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.104 AC: 3024 AN: 28950

American (AMR) AF: 0.0475 AC: 1991 AN: 41956

Ashkenazi Jewish (ASJ) AF: 0.0209 AC: 524 AN: 25026

East Asian (EAS) AF: 0.138 AC: 4472 AN: 32422

South Asian (SAS) AF: 0.0248 AC: 2045 AN: 82372

European-Finnish (FIN) AF: 0.0185 AC: 938 AN: 50572

Middle Eastern (MID) AF: 0.0266 AC: 146 AN: 5498

European-Non Finnish (NFE) AF: 0.0159 AC: 16809 AN: 1055206

Other (OTH) AF: 0.0249 AC: 1413 AN: 56784

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000908 AC: 135 AN: 148620 Hom.: 0 Cov.: 0 AF XY: 0.000898 AC XY: 65 AN XY: 72344

African (AFR) AF: 0.00213 AC: 86 AN: 40426

American (AMR) AF: 0.00121 AC: 18 AN: 14926

Ashkenazi Jewish (ASJ) AF: 0.000291 AC: 1 AN: 3438

East Asian (EAS) AF: 0.000400 AC: 2 AN: 5004

South Asian (SAS) AF: 0.000654 AC: 3 AN: 4590

European-Finnish (FIN) AF: 0.00119 AC: 12 AN: 10048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000179 AC: 12 AN: 66956

Other (OTH) AF: 0.000487 AC: 1 AN: 2052

Alfa AF: 0.0193 Hom.: 224

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs71019410; hg19: chr10-88458996;