11-65554255-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_001130144.3(LTBP3):c.457G>A(p.Gly153Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000703 in 1,609,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00072 ( 0 hom. )

Consequence

LTBP3
NM_001130144.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.128

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023158193).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00054 (82/151876) while in subpopulation NFE AF= 0.00087 (59/67854). AF 95% confidence interval is 0.000691. There are 0 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP3	NM_001130144.3 link	c.457G>A	p.Gly153Ser	missense_variant	Exon 2 of 28	ENST00000301873.11	NP_001123616.1	Q9NS15-1Q8WYU6
LTBP3	NM_021070.4 link	c.457G>A	p.Gly153Ser	missense_variant	Exon 2 of 27		NP_066548.2	Q9NS15-2Q8WYU6
LTBP3	NM_001164266.1 link	c.106G>A	p.Gly36Ser	missense_variant	Exon 2 of 27		NP_001157738.1	Q9NS15B9EG76Q8WYU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP3	ENST00000301873.11 link	c.457G>A	p.Gly153Ser	missense_variant	Exon 2 of 28	2	NM_001130144.3	ENSP00000301873.5		Q9NS15-1

Frequencies

GnomAD3 genomes

AF:

0.000540

AC:

AN:

151758

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000387

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000869

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000378

AC:

AN:

229956

Hom.:

AF XY:

0.000416

AC XY:

AN XY:

127534

show subpopulations

Gnomad AFR exome

AF:

0.000595

Gnomad AMR exome

AF:

0.000266

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000571

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000649

Gnomad OTH exome

AF:

0.000528

GnomAD4 exome

AF:

0.000720

AC:

1049

AN:

1457476

Hom.:

Cov.:

AF XY:

0.000731

AC XY:

530

AN XY:

725082

show subpopulations

Gnomad4 AFR exome

AF:

0.000688

Gnomad4 AMR exome

AF:

0.000405

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.000118

Gnomad4 NFE exome

AF:

0.000860

Gnomad4 OTH exome

AF:

0.000549

GnomAD4 genome

AF:

0.000540

AC:

AN:

151876

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.000386

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000870

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000807

Hom.:

Bravo

AF:

0.000574

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000251

AC:

ExAC

AF:

0.000261

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 22, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4_strong -

Brachyolmia-amelogenesis imperfecta syndrome

Uncertain:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 153 of the LTBP3 protein (p.Gly153Ser). This variant is present in population databases (rs373381192, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with LTBP3-related conditions. ClinVar contains an entry for this variant (Variation ID: 464027). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Inborn genetic diseases

Uncertain:1

Feb 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.457G>A (p.G153S) alteration is located in exon 2 (coding exon 2) of the LTBP3 gene. This alteration results from a G to A substitution at nucleotide position 457, causing the glycine (G) at amino acid position 153 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

LTBP3-related disorder

Uncertain:1

Aug 23, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LTBP3 c.457G>A variant is predicted to result in the amino acid substitution p.Gly153Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.068% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-65321726-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.37

CADD

Benign

8.2

DANN

Benign

0.68

DEOGEN2

Benign

0.087

.;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.68

T;T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.023

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.46

N;N;.

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.67

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.60

T;T;T

Sift4G

Benign

0.47

T;T;.

Polyphen

0.0030

B;B;B

Vest4

0.22

MVP

0.77

ClinPred

0.0021

GERP RS

-2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.032

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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