rs397517224

chr10-86681644-C-Achr10-86681644-C-Gchr10-86681644-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007078.3(LDB3):c.530C>A(p.Ala177Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A177V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.487

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16545832).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_007078.3	c.530C>A	p.Ala177Asp	missense_variant	5/14	ENST00000361373.9
LDB3	NM_001368067.1	c.321+1487C>A		intron_variant		ENST00000263066.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000361373.9	c.530C>A	p.Ala177Asp	missense_variant	5/14	1	NM_007078.3	P4
LDB3	ENST00000263066.11	c.321+1487C>A		intron_variant		1	NM_001368067.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460846 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726738

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000225 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 08, 2008

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	16
Dann	Uncertain	0.98
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.79	T;.;T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.17	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M;M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.2	N;.;N;N;.;N
REVEL	Benign	0.074
Sift	Uncertain	0.028	D;.;T;T;.;D
Sift4G	Benign	0.087	T;T;T;T;T;T
Polyphen		0.23, 0.55, 0.47	.;.;B;.;P;P
Vest4		0.42
MutPred		0.26		Gain of solvent accessibility (P = 0.0354);Gain of solvent accessibility (P = 0.0354);Gain of solvent accessibility (P = 0.0354);Gain of solvent accessibility (P = 0.0354);Gain of solvent accessibility (P = 0.0354);Gain of solvent accessibility (P = 0.0354);
MVP		0.71
MPC		0.34
ClinPred		0.28	T
GERP RS		4.9
Varity_R		0.13
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs397517224; hg19: chr10-88441401;