ENST00000308370.11:c.365delT
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000308370.11(LTBP4):c.365delT(p.Leu122ArgfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,261,218 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
ENST00000308370.11 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LTBP4 | ENST00000308370.11 | c.365delT | p.Leu122ArgfsTer15 | frameshift_variant | Exon 4 of 33 | 1 | ENSP00000311905.8 | |||
LTBP4 | ENST00000204005.13 | c.254delT | p.Leu85ArgfsTer15 | frameshift_variant | Exon 4 of 33 | 1 | ENSP00000204005.10 | |||
LTBP4 | ENST00000593738.1 | n.108delT | non_coding_transcript_exon_variant | Exon 1 of 2 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000919 AC: 14AN: 152266Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000114 AC: 3AN: 26376Hom.: 0 AF XY: 0.0000823 AC XY: 1AN XY: 12148
GnomAD4 exome AF: 0.000142 AC: 157AN: 1108952Hom.: 0 Cov.: 30 AF XY: 0.000150 AC XY: 79AN XY: 525768
GnomAD4 genome AF: 0.0000919 AC: 14AN: 152266Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74390
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Has not been previously published as pathogenic or benign in association with a LTBP4-related disorder to our knowledge; Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25714468, 28654958, 30487145, 29565423, 29030401, 31256874, 31589614) -
This sequence change creates a premature translational stop signal (p.Leu85Argfs*15) in the LTBP4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LTBP4 are known to be pathogenic (PMID: 19836010, 22829427). This variant is present in population databases (rs747013505, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with LTBP4-related conditions. ClinVar contains an entry for this variant (Variation ID: 189236). For these reasons, this variant has been classified as Pathogenic. -
Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies Pathogenic:1
The Leu85ArgfsX15 variant in LTBP4 has not been previously reported in individuals with autosomal recessive cutis laxa type I, but has been identified in 1/5840 of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 85 and lead to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of LTBP4 function has previously been desribed in homozygous and compound heterozygous individuals with autosomal recessive cutis laxa type IC (Urban 2009, Callewaert 2013). In summary, this variant meets our criteria to be classified as pathogenic for autosomal recessive cutis laxa type IC (http://pcpgm.partners.org/LMM). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at