rs786205350

Positions:

• chr10-86716425-G-A
• chr10-86716425-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_007078.3(LDB3):​c.1330G>A​(p.Ala444Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A444P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.985

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06216824).
• BP6: Variant 10-86716425-G-A is Benign according to our data. Variant chr10-86716425-G-A is described in ClinVar as [Benign]. Clinvar id is 192189.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDB3	NM_007078.3	c.1330G>A	p.Ala444Thr	missense_variant	10/14	ENST00000361373.9	NP_009009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9	c.1330G>A	p.Ala444Thr	missense_variant	10/14	1	NM_007078.3	ENSP00000355296	P4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.16	.;.;T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.85	T;.;T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.062	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.32	.;.;N;.
MutationTaster	Benign	1.0	D;N;N;N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.41	N;.;N;N
REVEL	Benign	0.063
Sift	Benign	0.42	T;.;T;T
Sift4G	Benign	0.49	T;T;T;T
Polyphen		0.064, 0.0	.;.;B;B
Vest4		0.18
MutPred		0.28		.;.;Gain of glycosylation at A444 (P = 0);.;
MVP		0.57
MPC		0.19
ClinPred		0.073	T
GERP RS		2.0
Varity_R		0.033
gMVP		0.22

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: rs786205350; hg19: chr10-88476182;