rs267607228

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001042545.2(LTBP4):​c.2481C>A​(p.Cys827Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LTBP4
NM_001042545.2 stop_gained

Scores

2
4
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: -0.593
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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;
PP5
Variant 19-40613453-C-A is Pathogenic according to our data. Variant chr19-40613453-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 5397.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LTBP4NM_001042545.2 linkuse as main transcriptc.2481C>A p.Cys827Ter stop_gained 17/30 ENST00000396819.8 NP_001036010.1
LTBP4NM_001042544.1 linkuse as main transcriptc.2682C>A p.Cys894Ter stop_gained 20/33 NP_001036009.1
LTBP4NM_003573.2 linkuse as main transcriptc.2571C>A p.Cys857Ter stop_gained 20/33 NP_003564.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LTBP4ENST00000396819.8 linkuse as main transcriptc.2481C>A p.Cys827Ter stop_gained 17/301 NM_001042545.2 ENSP00000380031 P3Q8N2S1-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000440
AC:
1
AN:
227046
Hom.:
0
AF XY:
0.00000812
AC XY:
1
AN XY:
123206
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000308
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS 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:
6.90e-7
AC:
1
AN:
1449584
Hom.:
0
Cov.:
34
AF XY:
0.00000139
AC XY:
1
AN XY:
720024
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000231
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 01, 2009- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.52
CADD
Pathogenic
35
DANN
Uncertain
0.99
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Uncertain
0.79
D
MutationTaster
Benign
1.0
A;A;A;D
Vest4
0.82
GERP RS
3.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs267607228; hg19: chr19-41119359; API