Genetic Variant NM_007078.3:c.295C>A (chr10-86680131-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_007078.3(LDB3):c.295C>A(p.Pro99Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P99S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LDB3
NM_007078.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.83

Variant links:

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]

LDB3 links:

ENSG00000289258 (HGNC:):

ENSG00000289258 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34776586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_007078.3 link	c.295C>A	p.Pro99Thr	missense_variant	Exon 4 of 14	ENST00000361373.9	NP_009009.1	O75112-1
LDB3	NM_001368067.1 link	c.295C>A	p.Pro99Thr	missense_variant	Exon 4 of 9	ENST00000263066.11	NP_001354996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LDB3	ENST00000361373.9 link	c.295C>A	p.Pro99Thr	missense_variant	Exon 4 of 14	1	NM_007078.3	ENSP00000355296.3	O75112-1
LDB3	ENST00000263066.11 link	c.295C>A	p.Pro99Thr	missense_variant	Exon 4 of 9	1	NM_001368067.1	ENSP00000263066.7	O75112-6
ENSG00000289258	ENST00000443292.2 link	c.1804C>A	p.Pro602Thr	missense_variant	Exon 14 of 18	1		ENSP00000393132.2	C9JWU6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727234

show subpopulations

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

0.00047

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

.;.;.;D;T;.;.;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.91

D;.;D;D;D;D;D;D

M_CAP

Uncertain

0.099

MetaRNN

Benign

0.35

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.38

MutationAssessor

Pathogenic

2.9

M;M;M;M;.;M;M;M

PrimateAI

Uncertain

0.48

PROVEAN

Pathogenic

-4.6

D;.;D;D;D;.;D;D

REVEL

Benign

0.21

Sift

Benign

0.072

T;.;D;D;D;.;D;D

Sift4G

Benign

0.13

T;T;T;T;T;T;T;T

Polyphen

0.66, 1.0, 0.96, 0.36, 0.87

.;.;P;D;.;D;B;P

Vest4

0.46

MutPred

0.38

Gain of glycosylation at P99 (P = 0.0218);Gain of glycosylation at P99 (P = 0.0218);Gain of glycosylation at P99 (P = 0.0218);Gain of glycosylation at P99 (P = 0.0218);Gain of glycosylation at P99 (P = 0.0218);Gain of glycosylation at P99 (P = 0.0218);Gain of glycosylation at P99 (P = 0.0218);Gain of glycosylation at P99 (P = 0.0218);

MVP

0.84

MPC

0.46

ClinPred

0.98

GERP RS

5.3

Varity_R

0.21

gMVP

0.59

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over