rs80338755
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000213.5(ITGB4):c.182G>A(p.Cys61Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,614,052 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
ITGB4
NM_000213.5 missense
NM_000213.5 missense
Scores
11
1
2
Clinical Significance
Conservation
PhyloP100: 4.14
Genes affected
ITGB4 (HGNC:6158): (integrin subunit beta 4) Integrins are heterodimers comprised of alpha and beta subunits, that are noncovalently associated transmembrane glycoprotein receptors. Different combinations of alpha and beta polypeptides form complexes that vary in their ligand-binding specificities. Integrins mediate cell-matrix or cell-cell adhesion, and transduced signals that regulate gene expression and cell growth. This gene encodes the integrin beta 4 subunit, a receptor for the laminins. This subunit tends to associate with alpha 6 subunit and is likely to play a pivotal role in the biology of invasive carcinoma. Mutations in this gene are associated with epidermolysis bullosa with pyloric atresia. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.981
PP5
?
Variant 17-75727423-G-A is Pathogenic according to our data. Variant chr17-75727423-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ITGB4 | NM_000213.5 | c.182G>A | p.Cys61Tyr | missense_variant | 4/40 | ENST00000200181.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ITGB4 | ENST00000200181.8 | c.182G>A | p.Cys61Tyr | missense_variant | 4/40 | 1 | NM_000213.5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152252Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249792Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135500
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GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461682Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14AN XY: 727160
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152370Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74514
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Junctional epidermolysis bullosa with pyloric atresia Pathogenic:2Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1998 | - - |
Pathogenic, criteria provided, single submitter | research | Biomedical Innovation Departament, CIEMAT | Mar 21, 2016 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 05, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 61 of the ITGB4 protein (p.Cys61Tyr). This variant is present in population databases (rs80338755, gnomAD 0.003%). This missense change has been observed in individuals with epidermolysis bullosa with pyloric atresia (PMID: 9792864, 16473856). ClinVar contains an entry for this variant (Variation ID: 14734). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ITGB4 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 21, 2022 | Recurrent pathogenic variant commonly seen in Hispanic individuals in the United States with EB-PA (Varki et al., 2006); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 11328943, 9792864, 16473856, 18779879, 20301336) - |
See cases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Personalized Medicine, Children's Hospital Los Angeles | Dec 21, 2022 | - - |
Junctional epidermolysis bullosa with pyloric atresia;C5676956:Epidermolysis bullosa, junctional 5A, intermediate Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 05, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H
MutationTaster
Benign
A;A;A;A;A
PrimateAI
Uncertain
T
Sift4G
Pathogenic
D;D;D;D
Polyphen
1.0
.;D;.;D
Vest4
MVP
MPC
1.3
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