rs144666367
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_StrongBS2
The NM_002640.4(SERPINB8):c.850C>T(p.Arg284*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000452 in 1,614,170 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00038 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00046 ( 2 hom. )
Consequence
SERPINB8
NM_002640.4 stop_gained
NM_002640.4 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 0.494
Genes affected
SERPINB8 (HGNC:8952): (serpin family B member 8) The protein encoded by this gene is a member of the ov-serpin family of serine protease inhibitors. The encoded protein is produced by platelets and can bind to and inhibit the function of furin, a serine protease involved in platelet functions. In addition, this protein has been found to enhance the mechanical stability of cell-cell adhesion in the skin, and defects in this gene have been associated with an autosomal-recessive form of exfoliative ichthyosis. [provided by RefSeq, Jan 2017]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.244 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SERPINB8 | NM_002640.4 | c.850C>T | p.Arg284* | stop_gained | Exon 7 of 7 | ENST00000397985.7 | NP_002631.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.000381 AC: 58AN: 152164Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000612 AC: 154AN: 251494Hom.: 0 AF XY: 0.000633 AC XY: 86AN XY: 135920
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GnomAD4 exome AF: 0.000459 AC: 671AN: 1461888Hom.: 2 Cov.: 30 AF XY: 0.000457 AC XY: 332AN XY: 727246
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GnomAD4 genome 0.000381 AC: 58AN: 152282Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28AN XY: 74468
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:2Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Peeling skin syndrome 5 Pathogenic:2Uncertain:1
| Likely pathogenic, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | NM_002640.3:c.850C>T in the SERPINB8 gene has an allele frequency of 0.012 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant is located in the last exon and may not lead to nonsense-mediated mRNA decay. It was detected in individual with autosomal recessive Peeling skin syndrome 5 in a pedigree, three homozygous c.850C>T, five carriers. And their parents are carriers (PMID: 27476651). The patient's phenotype is highly specific for SERPINB8 gene(PMID: 27476651). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PM3_Supporting; PP4; PP1_Strong. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 13, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 04, 2023 | - - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 01, 2024 | This sequence change creates a premature translational stop signal (p.Arg284*) in the SERPINB8 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 91 amino acid(s) of the SERPINB8 protein. This variant is present in population databases (rs144666367, gnomAD 1.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with exfoliative ichthyosis (PMID: 27476651). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 254200). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
Vest4
GERP RS
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