10-86668578-T-C

Variant names:

• chr10-86668578-T-C
• rs2803558
• NM_007078.3:c.-24+8T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001171610.2(LDB3):​c.-24+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.685 in 849,512 control chromosomes in the GnomAD database, including 200,676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (39117 hom., cov: 34)
  • Exomes 𝑓: 0.68 (161559 hom.)
• Consequence: LDB3 NM_001171610.2 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.36
• Publications: 12 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=-0.85).
• BP6: Variant 10-86668578-T-C is Benign according to our data. Variant chr10-86668578-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001171610.2. 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.-24+8T>C		splice_region intron	N/A	NP_009009.1
	LDB3	NM_001368067.1	MANE Plus Clinical	c.-24+8T>C		splice_region intron	N/A	NP_001354996.1
	LDB3	NM_001080116.1		c.-114T>C		5_prime_UTR	Exon 1 of 8	NP_001073585.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB3	ENST00000361373.9	TSL:1 MANE Select	c.-24+8T>C		splice_region intron	N/A	ENSP00000355296.3
	LDB3	ENST00000263066.11	TSL:1 MANE Plus Clinical	c.-24+8T>C		splice_region intron	N/A	ENSP00000263066.7
	ENSG00000289258	ENST00000443292.2	TSL:1	c.1487-91T>C		intron	N/A	ENSP00000393132.2

Frequencies

GnomAD3 genomes AF: 0.713 AC: 108394 AN: 152120 Hom.: 39067 Cov.: 34

Gnomad AFR AF: 0.816

Gnomad AMI AF: 0.832

Gnomad AMR AF: 0.632

Gnomad ASJ AF: 0.728

Gnomad EAS AF: 0.806

Gnomad SAS AF: 0.723

Gnomad FIN AF: 0.690

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.662

Gnomad OTH AF: 0.665

GnomAD4 exome AF: 0.679 AC: 473481 AN: 697274 Hom.: 161559 Cov.: 9 AF XY: 0.679 AC XY: 254191 AN XY: 374114

African (AFR) AF: 0.817 AC: 15482 AN: 18956

American (AMR) AF: 0.591 AC: 24227 AN: 40966

Ashkenazi Jewish (ASJ) AF: 0.719 AC: 15230 AN: 21190

East Asian (EAS) AF: 0.804 AC: 28527 AN: 35464

South Asian (SAS) AF: 0.707 AC: 49166 AN: 69550

European-Finnish (FIN) AF: 0.690 AC: 30668 AN: 44446

Middle Eastern (MID) AF: 0.705 AC: 3042 AN: 4312

European-Non Finnish (NFE) AF: 0.662 AC: 282737 AN: 426866

Other (OTH) AF: 0.687 AC: 24402 AN: 35524

GnomAD4 genome AF: 0.713 AC: 108493 AN: 152238 Hom.: 39117 Cov.: 34 AF XY: 0.716 AC XY: 53317 AN XY: 74440

African (AFR) AF: 0.816 AC: 33927 AN: 41560

American (AMR) AF: 0.631 AC: 9653 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.728 AC: 2528 AN: 3472

East Asian (EAS) AF: 0.807 AC: 4179 AN: 5180

South Asian (SAS) AF: 0.723 AC: 3487 AN: 4824

European-Finnish (FIN) AF: 0.690 AC: 7312 AN: 10602

Middle Eastern (MID) AF: 0.701 AC: 206 AN: 294

European-Non Finnish (NFE) AF: 0.662 AC: 45036 AN: 67992

Other (OTH) AF: 0.666 AC: 1406 AN: 2112

Alfa AF: 0.626 Hom.: 2037

Bravo AF: 0.709

Asia WGS AF: 0.760 AC: 2642 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Dilated cardiomyopathy 1C (2)
-	-	2	Myofibrillar myopathy 4 (2)
-	-	1	Left ventricular noncompaction cardiomyopathy (1)
-	-	1	Myofibrillar Myopathy, Dominant (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.046
DANN	Benign	0.41
PhyloP100		-1.4
PromoterAI		0.021	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2803558; hg19: chr10-88428335;