chr10-86668637-C-A

Variant names:

• chr10-86668637-C-A
• rs34972863
• ENST00000372066.8:c.-55C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001080116.1(LDB3):​c.-55C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00415 in 1,394,170 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (41 hom.)
• Consequence: LDB3 NM_001080116.1 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 1.17
• 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):

• dilated cardiomyopathy

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: ClinGen
• myofibrillar myopathy 4

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00316 (481/152290) while in subpopulation SAS AF = 0.0108 (52/4824). AF 95% confidence interval is 0.00844. There are 3 homozygotes in GnomAd4. There are 246 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080116.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB3	NM_007078.3	MANE Select	c.-23-32C>A		intron	N/A	NP_009009.1	O75112-1
	LDB3	NM_001368067.1	MANE Plus Clinical	c.-23-32C>A		intron	N/A	NP_001354996.1	A0A0S2Z530
	LDB3	NM_001080116.1		c.-55C>A		5_prime_UTR	Exon 1 of 8	NP_001073585.1	A0A0S2Z530

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB3	ENST00000372066.8	TSL:1	c.-55C>A		5_prime_UTR	Exon 1 of 8	ENSP00000361136.3	O75112-6
	LDB3	ENST00000361373.9	TSL:1 MANE Select	c.-23-32C>A		intron	N/A	ENSP00000355296.3	O75112-1
	LDB3	ENST00000263066.11	TSL:1 MANE Plus Clinical	c.-23-32C>A		intron	N/A	ENSP00000263066.7	O75112-6

Frequencies

GnomAD3 genomes AF: 0.00316 AC: 481 AN: 152172 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00357

Gnomad OTH AF: 0.00383

GnomAD4 exome AF: 0.00427 AC: 5301 AN: 1241880 Hom.: 41 Cov.: 18 AF XY: 0.00469 AC XY: 2954 AN XY: 629688

African (AFR) AF: 0.000652 AC: 19 AN: 29142

American (AMR) AF: 0.00223 AC: 99 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 755 AN: 24756

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38632

South Asian (SAS) AF: 0.0117 AC: 963 AN: 82012

European-Finnish (FIN) AF: 0.0000770 AC: 4 AN: 51978

Middle Eastern (MID) AF: 0.0164 AC: 87 AN: 5294

European-Non Finnish (NFE) AF: 0.00336 AC: 3070 AN: 912520

Other (OTH) AF: 0.00571 AC: 303 AN: 53090

GnomAD4 genome AF: 0.00316 AC: 481 AN: 152290 Hom.: 3 Cov.: 33 AF XY: 0.00330 AC XY: 246 AN XY: 74464

African (AFR) AF: 0.000529 AC: 22 AN: 41578

American (AMR) AF: 0.00190 AC: 29 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0346 AC: 120 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00357 AC: 243 AN: 68014

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00302 Hom.: 0

Bravo AF: 0.00292

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	14
DANN	Benign	0.76
PhyloP100		1.2
PromoterAI		-0.084	Neutral
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: rs34972863; hg19: chr10-88428394;