rs397517214

chr10-86716548-G-Achr10-86716548-G-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.1453G>A(p.Ala485Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000066 in 151,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. A485S) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.483

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=0.09509316).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_007078.3	c.1453G>A	p.Ala485Thr	missense_variant	10/14	ENST00000361373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000361373.9	c.1453G>A	p.Ala485Thr	missense_variant	10/14	1	NM_007078.3	P4

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151508 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249188 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151508 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 73948

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	13
Dann	Uncertain	0.98
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.86	D;.;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.095	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.94	D;D;D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.91	N;.;N;N
REVEL	Benign	0.036
Sift	Benign	0.72	T;.;T;T
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.40, 0.0	.;.;B;B
Vest4		0.13
MutPred		0.21		.;.;Gain of glycosylation at A485 (P = 0.0012);.;
MVP		0.61
MPC		0.19
ClinPred		0.064	T
GERP RS		2.2
Varity_R		0.032
gMVP		0.32

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: rs397517214; hg19: chr10-88476305;