rs28403592

Positions:

chr11-65553238-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001130144.3(LTBP3):c.989C>T(p.Pro330Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000578 in 1,614,106 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00057 ( 2 hom. )

Consequence

LTBP3
NM_001130144.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 4.84

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0072580874).

BP6

Variant 11-65553238-G-A is Benign according to our data. Variant chr11-65553238-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 548546.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000644 (98/152268) while in subpopulation EAS AF= 0.00655 (34/5188). AF 95% confidence interval is 0.00482. There are 0 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LTBP3	NM_001130144.3 linkuse as main transcript	c.989C>T	p.Pro330Leu	missense_variant	5/28	ENST00000301873.11	NP_001123616.1
LTBP3	NM_021070.4 linkuse as main transcript	c.989C>T	p.Pro330Leu	missense_variant	5/27		NP_066548.2
LTBP3	NM_001164266.1 linkuse as main transcript	c.638C>T	p.Pro213Leu	missense_variant	5/27		NP_001157738.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTBP3	ENST00000301873.11 linkuse as main transcript	c.989C>T	p.Pro330Leu	missense_variant	5/28	2	NM_001130144.3	ENSP00000301873	P1	Q9NS15-1

Frequencies

GnomAD3 genomes

AF:

0.000651

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00654

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00167

AC:

419

AN:

251370

Hom.:

AF XY:

0.00132

AC XY:

179

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00651

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00892

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000571

AC:

835

AN:

1461838

Hom.:

Cov.:

AF XY:

0.000513

AC XY:

373

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00608

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00791

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000192

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000644

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00655

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000637

Hom.:

Bravo

AF:

0.00112

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00140

AC:

170

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Geleophysic dysplasia 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Brachyolmia-amelogenesis imperfecta syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 01, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

LTBP3: BS1 -

LTBP3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

.;T;T;T

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.89

D;D;D;D

M_CAP

Benign

0.054

MetaRNN

Benign

0.0073

T;T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.69

N;N;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.10

T;T;T;T

Sift4G

Benign

0.16

T;T;.;.

Polyphen

0.34

B;P;B;.

Vest4

0.50

MVP

0.75

ClinPred

0.019

GERP RS

2.8

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.7

Varity_R

0.052

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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