17-75727423-G-A
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
Consequence
NM_000213.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ITGB4 | NM_000213.5 | c.182G>A | p.Cys61Tyr | missense_variant | Exon 4 of 40 | ENST00000200181.8 | NP_000204.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152252Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249792Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135500
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461682Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14AN XY: 727160
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152370Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74514
ClinVar
Submissions by phenotype
Junctional epidermolysis bullosa with pyloric atresia Pathogenic:2Other:1
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not provided Pathogenic:2
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) -
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. -
See cases Pathogenic:1
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Junctional epidermolysis bullosa with pyloric atresia;C5676956:Epidermolysis bullosa, junctional 5A, intermediate Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at