Variant 11-65539105-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001130144.3(LTBP3):c.3887C>T(p.Ala1296Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000153 in 1,309,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

LTBP3
NM_001130144.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.95

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.057642072).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LTBP3	NM_001130144.3 linkuse as main transcript	c.3887C>T	p.Ala1296Val	missense_variant	28/28	ENST00000301873.11	NP_001123616.1
LTBP3	NM_021070.4 linkuse as main transcript	c.3746C>T	p.Ala1249Val	missense_variant	27/27		NP_066548.2
LTBP3	NM_001164266.1 linkuse as main transcript	c.3395C>T	p.Ala1132Val	missense_variant	27/27		NP_001157738.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTBP3	ENST00000301873.11 linkuse as main transcript	c.3887C>T	p.Ala1296Val	missense_variant	28/28	2	NM_001130144.3	ENSP00000301873	P1	Q9NS15-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000153

AC:

AN:

1309844

Hom.:

Cov.:

AF XY:

0.00000156

AC XY:

AN XY:

642894

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000343

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.65e-7

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

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2023

The p.A1296V variant (also known as c.3887C>T), located in coding exon 28 of the LTBP3 gene, results from a C to T substitution at nucleotide position 3887. The alanine at codon 1296 is replaced by valine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

.;T;.;.;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.090

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.86

D;D;D;D;D

M_CAP

Benign

0.047

MetaRNN

Benign

0.058

T;T;T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.27

.;N;.;.;.

MutationTaster

Benign

0.89

N;N;N;N;N;N

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.020

N;N;N;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.17

T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0010

B;B;.;.;B

Vest4

0.094

MutPred

0.32

.;Loss of glycosylation at S1291 (P = 0.1653);.;.;.;

MVP

0.76

ClinPred

0.15

GERP RS

4.8

Varity_R

0.075

gMVP

0.41

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over