10-86668695-T-C

Variant names:

• chr10-86668695-T-C
• rs1564626023
• NM_007078.3:c.4T>C

Variant summary

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

The NM_007078.3(LDB3):​c.4T>C​(p.Ser2Pro) 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 1,460,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01

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.4T>C	p.Ser2Pro	missense_variant	Exon 2 of 14	ENST00000361373.9	NP_009009.1
LDB3	NM_001368067.1	c.4T>C	p.Ser2Pro	missense_variant	Exon 2 of 9	ENST00000263066.11	NP_001354996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9	c.4T>C	p.Ser2Pro	missense_variant	Exon 2 of 14	1	NM_007078.3	ENSP00000355296.3
LDB3	ENST00000263066.11	c.4T>C	p.Ser2Pro	missense_variant	Exon 2 of 9	1	NM_001368067.1	ENSP00000263066.7
ENSG00000289258	ENST00000443292.2	c.1513T>C	p.Ser505Pro	missense_variant	Exon 12 of 18	1		ENSP00000393132.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460966 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726828

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.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Sep 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S2P variant (also known as c.4T>C), located in coding exon 1 of the LDB3 gene, results from a T to C substitution at nucleotide position 4. The serine at codon 2 is replaced by proline, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	.;.;.;D;T;.;.;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.91	D;.;D;D;D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.64	N;N;N;N;.;N;N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.2	D;.;D;D;D;.;D;D
REVEL	Benign	0.11
Sift	Uncertain	0.0060	D;.;D;D;D;.;D;D
Sift4G	Uncertain	0.057	T;T;D;T;D;D;T;D
Polyphen		0.95, 0.97, 0.97, 0.95, 0.23	.;.;P;D;.;D;P;B
Vest4		0.48
MutPred		0.30		Loss of phosphorylation at S2 (P = 0.076);Loss of phosphorylation at S2 (P = 0.076);Loss of phosphorylation at S2 (P = 0.076);Loss of phosphorylation at S2 (P = 0.076);Loss of phosphorylation at S2 (P = 0.076);Loss of phosphorylation at S2 (P = 0.076);Loss of phosphorylation at S2 (P = 0.076);Loss of phosphorylation at S2 (P = 0.076);
MVP		0.76
MPC		0.59
ClinPred		0.85	D
GERP RS		4.4
Varity_R		0.42
gMVP		0.51

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: rs1564626023; hg19: chr10-88428452;