10-86687070-G-T

Variant names:

• chr10-86687070-G-T
• NM_001368067.1:c.346G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001368067.1(LDB3):​c.346G>T​(p.Ala116Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,461,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. A116T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LDB3 NM_001368067.1 missense, splice_region
• Scores: Splicing: ADA: 0.0001044
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.59

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17417511).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_001368067.1	c.346G>T	p.Ala116Ser	missense_variant, splice_region_variant	Exon 6 of 9	ENST00000263066.11	NP_001354996.1
LDB3	NM_007078.3	c.690-4826G>T		intron_variant	Intron 5 of 13	ENST00000361373.9	NP_009009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000263066.11	c.346G>T	p.Ala116Ser	missense_variant, splice_region_variant	Exon 6 of 9	1	NM_001368067.1	ENSP00000263066.7
LDB3	ENST00000361373.9	c.690-4826G>T		intron_variant	Intron 5 of 13	1	NM_007078.3	ENSP00000355296.3
ENSG00000289258	ENST00000443292.2	c.2199-4826G>T		intron_variant	Intron 15 of 17	1		ENSP00000393132.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461620 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727082

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Benign	0.71
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.45	T;.;T;T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Benign	-0.69	T
PROVEAN	Benign	-0.31	N;.;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.64	T;.;T;T;T
Sift4G	Benign	0.11	T;T;T;T;T
Polyphen		0.019, 0.015, 0.0020	.;.;B;B;B
Vest4		0.31
MutPred		0.23		.;.;Gain of disorder (P = 0.0522);.;Gain of disorder (P = 0.0522);
MVP		0.76
MPC		0.22
ClinPred		0.29	T
GERP RS		4.1
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-88446827; COSMIC: COSV99555687;