10-86668558-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_007078.3(LDB3):c.-36A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 767,794 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (23 hom., cov: 34)
  • Exomes 𝑓: 0.014 (97 hom.)
• Consequence: LDB3 NM_007078.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.07

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 10-86668558-A-G is Benign according to our data. Variant chr10-86668558-A-G is described in ClinVar as [Benign]. Clinvar id is 138105.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.012 (1827/152304) while in subpopulation NFE AF= 0.0192 (1307/68000). AF 95% confidence interval is 0.0184. There are 23 homozygotes in gnomad4. There are 846 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd at 1827 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_001368067.1	c.-36A>G		5_prime_UTR_variant	1/9	ENST00000263066.11
LDB3	NM_007078.3	c.-36A>G		5_prime_UTR_variant	1/14	ENST00000361373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000263066.11	c.-36A>G		5_prime_UTR_variant	1/9	1	NM_001368067.1
LDB3	ENST00000361373.9	c.-36A>G		5_prime_UTR_variant	1/14	1	NM_007078.3	P4

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1827 AN: 152186 Hom.: 23 Cov.: 34

Gnomad AFR AF: 0.00422

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.0115

GnomAD4 exome AF: 0.0141 AC: 8653 AN: 615490 Hom.: 97 Cov.: 7 AF XY: 0.0137 AC XY: 4550 AN XY: 333140

Gnomad4 AFR exome AF: 0.00431

Gnomad4 AMR exome AF: 0.00900

Gnomad4 ASJ exome AF: 0.0180

Gnomad4 EAS exome AF: 0.0000292

Gnomad4 SAS exome AF: 0.00195

Gnomad4 FIN exome AF: 0.00442

Gnomad4 NFE exome AF: 0.0197

Gnomad4 OTH exome AF: 0.0138

GnomAD4 genome AF: 0.0120 AC: 1827 AN: 152304 Hom.: 23 Cov.: 34 AF XY: 0.0114 AC XY: 846 AN XY: 74476

Gnomad4 AFR AF: 0.00421

Gnomad4 AMR AF: 0.0136

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00320

Gnomad4 NFE AF: 0.0192

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0163 Hom.: 7

Bravo AF: 0.0130

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 02, 2012

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	-0.78
Cadd	Benign	11
Dann	Benign	0.67

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2803557; hg19: chr10-88428315; COSMIC: COSV53940137; COSMIC: COSV53940137;