10-86680090-G-T

Variant names:

• chr10-86680090-G-T
• rs200420174
• NM_007078.3:c.254G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007078.3(LDB3):​c.254G>T​(p.Arg85Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,202 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R85C) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 33)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.40

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]

ENSG00000289258 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_007078.3	c.254G>T	p.Arg85Leu	missense_variant	Exon 4 of 14	ENST00000361373.9	NP_009009.1
LDB3	NM_001368067.1	c.254G>T	p.Arg85Leu	missense_variant	Exon 4 of 9	ENST00000263066.11	NP_001354996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9	c.254G>T	p.Arg85Leu	missense_variant	Exon 4 of 14	1	NM_007078.3	ENSP00000355296.3
LDB3	ENST00000263066.11	c.254G>T	p.Arg85Leu	missense_variant	Exon 4 of 9	1	NM_001368067.1	ENSP00000263066.7
ENSG00000289258	ENST00000443292.2	c.1763G>T	p.Arg588Leu	missense_variant	Exon 14 of 18	1		ENSP00000393132.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74344

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;.;.;D;T;.;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.5	M;M;M;M;.;M;M;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.9	D;.;D;D;D;.;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0060	D;.;D;D;D;.;D;D
Sift4G	Uncertain	0.041	D;D;D;D;D;D;D;D
Polyphen		0.98, 1.0, 0.98, 0.80, 1.0	.;.;D;D;.;D;P;D
Vest4		0.66
MutPred		0.36		Loss of solvent accessibility (P = 0.0098);Loss of solvent accessibility (P = 0.0098);Loss of solvent accessibility (P = 0.0098);Loss of solvent accessibility (P = 0.0098);Loss of solvent accessibility (P = 0.0098);Loss of solvent accessibility (P = 0.0098);Loss of solvent accessibility (P = 0.0098);Loss of solvent accessibility (P = 0.0098);
MVP		0.82
MPC		0.83
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.34
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs200420174; hg19: chr10-88439847;