NM_001042545.2:c.4037delC
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2
The NM_001042545.2(LTBP4):c.4037delC(p.Pro1346ArgfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,599,260 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
LTBP4
NM_001042545.2 frameshift
NM_001042545.2 frameshift
Scores
Not classified
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: -0.128
Publications
3 publications found
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 anomaliesInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 10 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LTBP4 | NM_001042545.2 | c.4037delC | p.Pro1346ArgfsTer16 | frameshift_variant | Exon 28 of 30 | ENST00000396819.8 | NP_001036010.1 | |
| LTBP4 | NM_001042544.1 | c.4238delC | p.Pro1413ArgfsTer16 | frameshift_variant | Exon 31 of 33 | NP_001036009.1 | ||
| LTBP4 | NM_003573.2 | c.4127delC | p.Pro1376ArgfsTer16 | frameshift_variant | Exon 31 of 33 | NP_003564.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LTBP4 | ENST00000396819.8 | c.4037delC | p.Pro1346ArgfsTer16 | frameshift_variant | Exon 28 of 30 | 1 | NM_001042545.2 | ENSP00000380031.5 |
Frequencies
GnomAD3 genomes 0.00000658 AC: 1AN: 152076Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152076
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
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Gnomad EAS
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Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
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Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD2 exomes AF: 0.00 AC: 0AN: 238774 AF XY: 0.00
GnomAD2 exomes
AF:
AC:
0
AN:
238774
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
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Gnomad ASJ exome
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Gnomad EAS exome
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Gnomad FIN exome
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Gnomad NFE exome
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Gnomad OTH exome
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GnomAD4 exome AF: 6.91e-7 AC: 1AN: 1447184Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1AN XY: 718036 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
1
AN:
1447184
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
718036
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33198
American (AMR)
AF:
AC:
0
AN:
43472
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25234
East Asian (EAS)
AF:
AC:
0
AN:
39380
South Asian (SAS)
AF:
AC:
0
AN:
84992
European-Finnish (FIN)
AF:
AC:
0
AN:
52900
Middle Eastern (MID)
AF:
AC:
0
AN:
5694
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1102690
Other (OTH)
AF:
AC:
0
AN:
59624
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.00000658 AC: 1AN: 152076Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74282 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
152076
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74282
show subpopulations
African (AFR)
AF:
AC:
1
AN:
41408
American (AMR)
AF:
AC:
0
AN:
15278
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5186
South Asian (SAS)
AF:
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
AC:
0
AN:
10602
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
0
AN:
67986
Other (OTH)
AF:
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.725
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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