NM_003784.4:c.796C>T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_003784.4(SERPINB7):c.796C>T(p.Arg266*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,605,018 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 Pathogenic (★★).
Frequency
Consequence
NM_003784.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SERPINB7 | ENST00000398019.7 | c.796C>T | p.Arg266* | stop_gained | Exon 8 of 8 | 1 | NM_003784.4 | ENSP00000381101.2 | ||
SERPINB7 | ENST00000336429.6 | c.796C>T | p.Arg266* | stop_gained | Exon 8 of 8 | 1 | ENSP00000337212.2 | |||
SERPINB7 | ENST00000546027.5 | c.796C>T | p.Arg266* | stop_gained | Exon 8 of 8 | 2 | ENSP00000444861.1 | |||
SERPINB7 | ENST00000540675.5 | c.745C>T | p.Arg249* | stop_gained | Exon 7 of 7 | 2 | ENSP00000444572.1 |
Frequencies
GnomAD3 genomes AF: 0.000322 AC: 49AN: 152092Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000550 AC: 134AN: 243522Hom.: 0 AF XY: 0.000510 AC XY: 67AN XY: 131500
GnomAD4 exome AF: 0.000243 AC: 353AN: 1452808Hom.: 0 Cov.: 29 AF XY: 0.000253 AC XY: 183AN XY: 722538
GnomAD4 genome AF: 0.000322 AC: 49AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25AN XY: 74422
ClinVar
Submissions by phenotype
Palmoplantar keratoderma, Nagashima type Pathogenic:8
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Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10% (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000102446, PMID:24207119, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000527, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
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NM_003784.3:c.796C>T in the SERPINB7 gene has an allele frequency of 0.007 Asia in East Asian subpopulation in the gnomAD database. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It was detected in individual with autosomal recessive Palmoplantar keratoderma, nagashima type, compound heterozygous with c.218_219del2ins12, c.455-1G>A, respectively (PMID: 24207119). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PVS1; PM3_Strong; PP4. -
This sequence change in SERPINB7 is a nonsense variant predicted to cause a premature stop codon, p.(Arg266*), that is predicted to escape nonsense-mediated decay and remove <10% of the protein (removes amino acids 226-380) in a gene where loss of function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.8% (347/44,860 alleles) in the East Asian population, which is higher than expected for a recessive disease. However, this variant is an East Asian founder mutation for Nagashima-type palmoplantar keratoderma. It has been reported in multiple affected individuals in the homozygous and compound heterozygous state (with at least one individual with a pathogenic variant on the second allele) and segregates with disease in at least one family (PMID: 24207119, 35178744). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PVS1_Strong, PP1, BS1. -
PM3_VeryStrong+PVS1_Strong -
not provided Pathogenic:3
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 115 amino acids are lost, and other loss-of-function variants have been reported in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 24514002, 27786350, 27663160, 27569382, 27543371, 27506501, 28211129, 29888704, 30256384, 30581033, 30833958, 30004585, 32406097, 31980526, 24077912, 34426522, 33362511, 32892407, 33914963, 34379845, 27666198, 24207119, 24773080) -
This sequence change creates a premature translational stop signal (p.Arg266*) in the SERPINB7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 115 amino acid(s) of the SERPINB7 protein. This variant is present in population databases (rs142859678, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with Nagashima-type palmoplantar keratoderma (NPPK) (PMID: 24207119, 24514002, 27543371, 27666198). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Japanese and Han Chinese ancestry (PMID: 24514002, 24773080). ClinVar contains an entry for this variant (Variation ID: 102446). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
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SERPINB7-related disorder Pathogenic:1
The SERPINB7 c.796C>T variant is predicted to result in premature protein termination (p.Arg266*). This variant has been reported to be causative for autosomal recessive Nagashima-type palmoplantar keratosis and has been described as a founder mutation in Asian populations (Kubo et al. 2013. PubMed ID: 24207119; Yin et al. 2014. PubMed ID: 24514002; Zhang et al. 2016. PubMed ID: 27666198). This variant is reported in 0.69% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-61471522-C-T). Nonsense variants in SERPINB7 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at