rs727505295

Positions:

• chr10-86668701-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007078.3(LDB3):​c.10A>C​(p.Ser4Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.57

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40515178).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDB3	NM_007078.3	c.10A>C	p.Ser4Arg	missense_variant	2/14	ENST00000361373.9	NP_009009.1
LDB3	NM_001368067.1	c.10A>C	p.Ser4Arg	missense_variant	2/9	ENST00000263066.11	NP_001354996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9	c.10A>C	p.Ser4Arg	missense_variant	2/14	1	NM_007078.3	ENSP00000355296	P4
LDB3	ENST00000263066.11	c.10A>C	p.Ser4Arg	missense_variant	2/9	1	NM_001368067.1	ENSP00000263066

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461046 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726862

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 06, 2014

- -

Myofibrillar myopathy 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 14, 2023

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 4 of the LDB3 protein (p.Ser4Arg). This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 180025). This missense change has been observed in individual(s) with left ventricular noncompaction (PMID: 33500567). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;.;.;D;T;.;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.92	D;.;D;D;D;D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.2	L;L;L;L;.;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.8	D;.;D;D;D;.;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D;.;D;D;D;.;T;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D
Polyphen		0.84, 0.99, 0.99, 0.80	.;.;P;D;.;D;D;P
Vest4		0.48
MutPred		0.51		Gain of methylation at S4 (P = 0.0254);Gain of methylation at S4 (P = 0.0254);Gain of methylation at S4 (P = 0.0254);Gain of methylation at S4 (P = 0.0254);Gain of methylation at S4 (P = 0.0254);Gain of methylation at S4 (P = 0.0254);Gain of methylation at S4 (P = 0.0254);Gain of methylation at S4 (P = 0.0254);
MVP		0.76
MPC		0.78
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.89
gMVP		0.56

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: rs727505295; hg19: chr10-88428458;