rs187448224

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001042545.2(LTBP4):c.4348G>C(p.Glu1450Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000726 in 1,514,236 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 (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000051 ( 0 hom. )

Consequence

LTBP4
NM_001042545.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.30

Publications

1 publications found

Variant links:

Genes affected

LTBP4 (HGNC:6717): (latent transforming growth factor beta binding protein 4) The protein encoded by this gene binds transforming growth factor beta (TGFB) as it is secreted and targeted to the extracellular matrix. TGFB is biologically latent after secretion and insertion into the extracellular matrix, and sheds TGFB and other proteins upon activation. Defects in this gene may be a cause of cutis laxa and severe pulmonary, gastrointestinal, and urinary abnormalities. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

LTBP4 Gene-Disease associations (from GenCC):

cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

LTBP4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.043471128).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP4	NM_001042545.2 link	c.4348G>C	p.Glu1450Gln	missense_variant	Exon 28 of 30	ENST00000396819.8	NP_001036010.1	Q8N2S1-2B3KXY6
LTBP4	NM_001042544.1 link	c.4549G>C	p.Glu1517Gln	missense_variant	Exon 31 of 33		NP_001036009.1	Q8N2S1-1B3KXY6
LTBP4	NM_003573.2 link	c.4438G>C	p.Glu1480Gln	missense_variant	Exon 31 of 33		NP_003564.2	Q8N2S1A0A0C4DH07B3KXY6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8 link	c.4348G>C	p.Glu1450Gln	missense_variant	Exon 28 of 30	1	NM_001042545.2	ENSP00000380031.5		Q8N2S1-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000558

AC:

AN:

143448

AF XY:

0.0000520

show subpopulations

Gnomad AFR exome

AF:

0.000442

Gnomad AMR exome

AF:

0.000170

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000514

AC:

AN:

1361902

Hom.:

Cov.:

AF XY:

0.00000749

AC XY:

AN XY:

667748

show subpopulations

African (AFR)

AF:

0.0000636

AC:

AN:

31452

American (AMR)

AF:

0.000116

AC:

AN:

34414

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22622

East Asian (EAS)

AF:

0.00

AC:

AN:

36850

South Asian (SAS)

AF:

0.00

AC:

AN:

74774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5376

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1065244

Other (OTH)

AF:

0.0000176

AC:

AN:

56778

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

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:

0.0000263

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41578

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

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:

0.0000712

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.000245

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000590

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 15, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Glu1517Gln variant in LTBP4 has not been previously reported in individual s with pulmonary disease, but has been identified in 0.26% (4/1354) of African c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs187448224). Computational prediction tools and conservation analys is are limited or unavailable for this variant. In summary, the clinical signifi cance of the p.Glu1517Gln variant is uncertain. -

not provided

Uncertain:1

Jul 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 228844). This variant has not been reported in the literature in individuals affected with LTBP4-related conditions. This variant is present in population databases (rs187448224, gnomAD 0.05%). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 1480 of the LTBP4 protein (p.Glu1480Gln). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.067

T;T;.;T

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.092

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.87

D;D;D;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.043

T;T;T;T

MetaSVM

Benign

-0.32

PhyloP100

4.3

PrimateAI

Uncertain

0.59

REVEL

Benign

0.24

Sift4G

Benign

0.18

T;T;T;T

Polyphen

0.98

.;D;.;.

Vest4

0.51

MVP

0.43

MPC

0.53

ClinPred

0.15

GERP RS

4.2

PromoterAI

-0.0072

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.081

gMVP

0.41

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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