Variant chr11-65539087-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001130144.3(LTBP3):c.3905G>T(p.Arg1302Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000798 in 1,253,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1302H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 8.0e-7 ( 0 hom. )

Consequence

LTBP3
NM_001130144.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.824

Variant links:

Genes affected

LTBP3 (HGNC:6716): (latent transforming growth factor beta binding protein 3) The protein encoded by this gene forms a complex with transforming growth factor beta (TGF-beta) proteins and may be involved in their subcellular localization. Activation of this complex requires removal of the encoded binding protein. This protein also may play a structural role in the extracellular matrix. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]

LTBP3 links:

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ACMG classification

Classification made for transcript

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=0.26306006).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LTBP3	NM_001130144.3 linkuse as main transcript	c.3905G>T	p.Arg1302Leu	missense_variant	28/28	ENST00000301873.11
LTBP3	NM_021070.4 linkuse as main transcript	c.3764G>T	p.Arg1255Leu	missense_variant	27/27
LTBP3	NM_001164266.1 linkuse as main transcript	c.3413G>T	p.Arg1138Leu	missense_variant	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTBP3	ENST00000301873.11 linkuse as main transcript	c.3905G>T	p.Arg1302Leu	missense_variant	28/28	2	NM_001130144.3	P1	Q9NS15-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.98e-7

AC:

AN:

1253650

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

612496

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:

0.0000308

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Brachyolmia-amelogenesis imperfecta syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 21, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with LTBP3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1302 of the LTBP3 protein (p.Arg1302Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

.;T;.;.;.

Eigen

Benign

0.059

Eigen_PC

Benign

0.063

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.90

D;D;D;D;D

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.26

T;T;T;T;T

MetaSVM

Uncertain

0.035

MutationAssessor

Benign

1.2

.;L;.;.;.

MutationTaster

Benign

0.80

D;D;D;D;N;N

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.8

N;N;N;N;N

REVEL

Uncertain

0.37

Sift

Uncertain

0.0060

D;D;D;D;T

Sift4G

Uncertain

0.024

D;D;T;D;T

Polyphen

0.95

P;D;.;.;D

Vest4

0.38

MutPred

0.35

.;Loss of MoRF binding (P = 0.0689);.;.;.;

MVP

0.80

ClinPred

0.77

GERP RS

4.9

Varity_R

0.23

gMVP

0.56

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over