rs553283319

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000308370.11(LTBP4):c.415A>G(p.Arg139Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000208 in 1,103,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

LTBP4
ENST00000308370.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.397

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11950484).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTBP4	NM_001042544.1 link	c.415A>G	p.Arg139Gly	missense_variant	Exon 4 of 33		NP_001036009.1	Q8N2S1-1B3KXY6
LTBP4	NM_003573.2 link	c.304A>G	p.Arg102Gly	missense_variant	Exon 4 of 33		NP_003564.2	Q8N2S1A0A0C4DH07B3KXY6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
LTBP4	ENST00000308370.11 link	c.415A>G	p.Arg139Gly	missense_variant	Exon 4 of 33	1	ENSP00000311905.8	Q8N2S1-1
LTBP4	ENST00000204005.13 link	c.304A>G	p.Arg102Gly	missense_variant	Exon 4 of 33	1	ENSP00000204005.10	A0A0C4DH07
LTBP4	ENST00000593738.1 link	n.158A>G		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000208

AC:

AN:

1103782

Hom.:

Cov.:

AF XY:

0.0000210

AC XY:

AN XY:

522588

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23088

American (AMR)

AF:

0.00

AC:

AN:

8590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14482

East Asian (EAS)

AF:

0.00

AC:

AN:

26630

South Asian (SAS)

AF:

0.00

AC:

AN:

21754

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36780

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4204

European-Non Finnish (NFE)

AF:

0.0000249

AC:

AN:

924150

Other (OTH)

AF:

0.00

AC:

AN:

44104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 24, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg139Gly variant in LTBP4 has not been previously reported in individuals with pulmonary disease. Data from large population studies is insufficient to a ssess the frequency of this variant. Computational prediction tools and conserva tion analysis do not provide strong support for or against an impact to the prot ein. In summary, the clinical significance of the p.Arg139Gly variant is uncerta in. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.020

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.044

T;T

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.66

T;T

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.0

.;N

PhyloP100

0.40

PrimateAI

Uncertain

0.76

PROVEAN

Benign

0.080

N;N

REVEL

Benign

0.25

Sift

Benign

0.20

T;D

Sift4G

Uncertain

0.024

D;D

Polyphen

0.0020

.;B

Vest4

0.37

MVP

0.62

MPC

1.0

ClinPred

0.40

GERP RS

3.5

Varity_R

0.23

gMVP

0.57

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over