rs45487699

Positions:

• chr10-86681680-C-G
• chr10-86681680-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_007078.3(LDB3):​c.566C>G​(p.Ser189Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. S189L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.32

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-86681680-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.40526298).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDB3	NM_007078.3	c.566C>G	p.Ser189Trp	missense_variant	5/14	ENST00000361373.9	NP_009009.1
LDB3	NM_001368067.1	c.321+1523C>G		intron_variant		ENST00000263066.11	NP_001354996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9	c.566C>G	p.Ser189Trp	missense_variant	5/14	1	NM_007078.3	ENSP00000355296.3
ENSG00000289258	ENST00000443292.2	c.2075C>G	p.Ser692Trp	missense_variant	15/18	1		ENSP00000393132.2
LDB3	ENST00000263066.11	c.321+1523C>G		intron_variant		1	NM_001368067.1	ENSP00000263066.7

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	.;.;T;T;.;.
Eigen	Benign	0.11
Eigen_PC	Benign	-0.0061
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.95	D;.;D;D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.41	T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.3	M;M;M;.;M;M
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.8	N;.;N;N;.;N
REVEL	Benign	0.21
Sift	Benign	0.18	T;.;T;T;.;T
Sift4G	Benign	0.14	T;T;T;D;D;D
Polyphen		0.95, 0.99, 1.0	.;.;P;.;D;D
Vest4		0.47
MutPred		0.39		Loss of disorder (P = 0.032);Loss of disorder (P = 0.032);Loss of disorder (P = 0.032);Loss of disorder (P = 0.032);Loss of disorder (P = 0.032);Loss of disorder (P = 0.032);
MVP		0.81
MPC		0.79
ClinPred		0.94	D
GERP RS		3.8
Varity_R		0.090
gMVP		0.78

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: rs45487699; hg19: chr10-88441437;