Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PP5_Moderate
The NM_000213.5(ITGB4):c.1660C>T(p.Arg554*) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.00000411 in 1,461,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
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]
ITGB4 Gene-Disease associations (from GenCC):
epidermolysis bullosa simplex
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
junctional epidermolysis bullosa with pyloric atresia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet, Ambry Genetics
junctional epidermolysis bullosa, non-Herlitz type
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
aplasia cutis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
epidermolysis bullosa simplex 5C, with pyloric atresia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
generalized junctional epidermolysis bullosa non-Herlitz type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
localized junctional epidermolysis bullosa, non-Herlitz type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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.
PP5
Variant 17-75736053-C-T is Pathogenic according to our data. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-75736053-C-T is described in CliVar as Pathogenic. Clinvar id is 14733.Status of the report is criteria_provided_single_submitter, 1 stars.