chr11-108509720-AG-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_015065.3(EXPH5):c.5786delC(p.Pro1929LeufsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,609,238 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_015065.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EXPH5 | ENST00000265843.9 | c.5786delC | p.Pro1929LeufsTer8 | frameshift_variant | Exon 6 of 6 | 1 | NM_015065.3 | ENSP00000265843.4 | ||
EXPH5 | ENST00000525344.5 | c.5765delC | p.Pro1922LeufsTer8 | frameshift_variant | Exon 7 of 7 | 1 | ENSP00000432546.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000815 AC: 2AN: 245334Hom.: 0 AF XY: 0.00000754 AC XY: 1AN XY: 132642
GnomAD4 exome AF: 0.0000240 AC: 35AN: 1457088Hom.: 1 Cov.: 32 AF XY: 0.0000262 AC XY: 19AN XY: 724774
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74328
ClinVar
Submissions by phenotype
Epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive Pathogenic:1
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not provided Pathogenic:1
Analysis of a skin biopsy from one affected sibling showed loss of EXPH5 immunostaining, disruption of keratinocyte adhesion within the lower epidermis, and an increased number of perinuclear vesicles (McGrath et al., 2012); Frameshift variant predicted to result in protein truncation as the last 61 amino acids are replaced with 7 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 23176819, 26211931, 34426522, 32176379, 33274474) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at