rs752311785

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001130144.3(LTBP3):c.751G>A(p.Glu251Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,561,526 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. E251G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

LTBP3
NM_001130144.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.16

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

brachyolmia-amelogenesis imperfecta syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
geleophysic dysplasia 3
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Acromicric dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
geleophysic dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LTBP3 links:

ENSG00000302197 (HGNC:):

ENSG00000302197 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18654111).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
LTBP3	NM_001130144.3 link	c.751G>A	p.Glu251Lys	missense_variant	Exon 3 of 28	ENST00000301873.11	NP_001123616.1
LTBP3	NM_021070.4 link	c.751G>A	p.Glu251Lys	missense_variant	Exon 3 of 27		NP_066548.2
LTBP3	NM_001164266.1 link	c.400G>A	p.Glu134Lys	missense_variant	Exon 3 of 27		NP_001157738.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP3	ENST00000301873.11 link	c.751G>A	p.Glu251Lys	missense_variant	Exon 3 of 28	2	NM_001130144.3	ENSP00000301873.5

Frequencies

GnomAD3 genomes

AF:

0.000119

AC:

AN:

151768

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000250

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000960

AC:

AN:

166588

AF XY:

0.0000876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000224

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000177

AC:

249

AN:

1409758

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

117

AN XY:

698106

show subpopulations

African (AFR)

AF:

0.0000610

AC:

AN:

32798

American (AMR)

AF:

0.00

AC:

AN:

38842

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25384

East Asian (EAS)

AF:

0.00

AC:

AN:

37824

South Asian (SAS)

AF:

0.00

AC:

AN:

81656

European-Finnish (FIN)

AF:

0.0000849

AC:

AN:

35316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.000217

AC:

237

AN:

1093400

Other (OTH)

AF:

0.000119

AC:

AN:

58856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000119

AC:

AN:

151768

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74084

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41296

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

67894

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000182

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.0000687

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Apr 16, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Brachyolmia-amelogenesis imperfecta syndrome

Uncertain:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 251 of the LTBP3 protein (p.Glu251Lys). This variant is present in population databases (rs752311785, gnomAD 0.02%). 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: 571639). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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

Nov 17, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.751G>A (p.E251K) alteration is located in exon 3 (coding exon 3) of the LTBP3 gene. This alteration results from a G to A substitution at nucleotide position 751, causing the glutamic acid (E) at amino acid position 251 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.059

.;T;T

Eigen

Benign

-0.097

Eigen_PC

Benign

-0.062

FATHMM_MKL

Benign

0.46

LIST_S2

Uncertain

0.88

D;D;T

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Benign

-0.39

MutationAssessor

Benign

0.20

N;N;.

PhyloP100

2.2

PrimateAI

Uncertain

0.77

PROVEAN

Benign

0.33

N;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.47

T;T;T

Sift4G

Benign

1.0

T;T;.

Polyphen

0.55

P;D;D

Vest4

0.35

MVP

0.86

ClinPred

0.13

GERP RS

4.3

Varity_R

0.13

gMVP

0.32

Mutation Taster

=70/30

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over