rs1555741927
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001042545.2(LTBP4):c.3485C>T(p.Ala1162Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,088 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
LTBP4
NM_001042545.2 missense, splice_region
NM_001042545.2 missense, splice_region
Scores
8
8
Clinical Significance
Conservation
PhyloP100: 1.44
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LTBP4 | NM_001042545.2 | c.3485C>T | p.Ala1162Val | missense_variant, splice_region_variant | 24/30 | ENST00000396819.8 | |
LTBP4 | NM_001042544.1 | c.3686C>T | p.Ala1229Val | missense_variant, splice_region_variant | 27/33 | ||
LTBP4 | NM_003573.2 | c.3575C>T | p.Ala1192Val | missense_variant, splice_region_variant | 27/33 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LTBP4 | ENST00000396819.8 | c.3485C>T | p.Ala1162Val | missense_variant, splice_region_variant | 24/30 | 1 | NM_001042545.2 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152122Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.00000753 AC: 11AN: 1460966Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726766
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152122Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74296
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 07, 2016 | The p.Ala1229Val variant in LTBP4 has not been previously reported in individual s with pulmonary disease or in large population studies. Computational predictio n tools and conservation analysis do not provide strong support for or against a n impact to the protein. This variant affects the first base of the exon. Varia nts at this position sometimes impact splicing; however, no such effect is predi cted by computational tools (this information is not predictive enough to determ ine pathogenicity). In summary, the clinical significance of the p.Ala1229Val va riant is uncertain. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
REVEL
Uncertain
Sift4G
Benign
T;T;T
Polyphen
1.0
.;D;.
Vest4
MutPred
0.73
.;Loss of disorder (P = 0.078);.;
MVP
MPC
0.34
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at