rs727504500

Positions:

• chr10-86679473-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_007078.3(LDB3):​c.200A>G​(p.Asn67Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.29

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 Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDB3	NM_007078.3	c.200A>G	p.Asn67Ser	missense_variant	3/14	ENST00000361373.9	NP_009009.1
LDB3	NM_001368067.1	c.200A>G	p.Asn67Ser	missense_variant	3/9	ENST00000263066.11	NP_001354996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9	c.200A>G	p.Asn67Ser	missense_variant	3/14	1	NM_007078.3	ENSP00000355296.3
LDB3	ENST00000263066.11	c.200A>G	p.Asn67Ser	missense_variant	3/9	1	NM_001368067.1	ENSP00000263066.7
ENSG00000289258	ENST00000443292.2	c.1709A>G	p.Asn570Ser	missense_variant	13/18	1		ENSP00000393132.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461802 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727196

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: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Apr 05, 2013

The Asn67Ser variant in LDB3 has not been reported in the literature nor previou sly identified by our laboratory. This variant has also not been identified in l arge European American and African American populations by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS), though it may be present in ot her populations. Computational analyses (biochemical amino acid properties, cons ervation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or a gainst an impact to the protein. At this time, additional information is needed to fully assess the clinical significance of this variant. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 13, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	.;.;.;T;T;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;.;D;D;D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.0	M;M;M;M;.;M;M;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.2	D;.;D;D;D;.;D;D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D;.;D;D;D;.;D;D
Sift4G	Pathogenic	0.0	D;D;T;D;D;D;D;D
Polyphen		1.0, 1.0, 1.0, 0.97	.;.;D;D;.;D;D;D
Vest4		0.72
MutPred		0.54		Gain of disorder (P = 0.0787);Gain of disorder (P = 0.0787);Gain of disorder (P = 0.0787);Gain of disorder (P = 0.0787);Gain of disorder (P = 0.0787);Gain of disorder (P = 0.0787);Gain of disorder (P = 0.0787);Gain of disorder (P = 0.0787);
MVP		0.76
MPC		0.69
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.74
gMVP		0.50

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: rs727504500; hg19: chr10-88439230;