rs577442939
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PVS1PM2PP3_StrongPP5
The NM_003784.4(SERPINB7):c.455-1G>A variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000304 in 1,510,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000032 ( 0 hom. )
Consequence
SERPINB7
NM_003784.4 splice_acceptor
NM_003784.4 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.16
Genes affected
SERPINB7 (HGNC:13902): (serpin family B member 7) This gene encodes a member of a family of proteins which function as protease inhibitors. Expression of this gene is upregulated in IgA nephropathy and mutations have been found to cause palmoplantar keratoderma, Nagashima type. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.8, offset of 1, new splice context is: tcaatttttttttcaaaaAGcaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 18-63798603-G-A is Pathogenic according to our data. Variant chr18-63798603-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 102448.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SERPINB7 | NM_003784.4 | c.455-1G>A | splice_acceptor_variant | ENST00000398019.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SERPINB7 | ENST00000398019.7 | c.455-1G>A | splice_acceptor_variant | 1 | NM_003784.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000201 AC: 3AN: 149440Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000256 AC: 5AN: 195598Hom.: 0 AF XY: 0.0000187 AC XY: 2AN XY: 107182
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GnomAD4 exome AF: 0.0000316 AC: 43AN: 1361136Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 18AN XY: 670074
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GnomAD4 genome ? AF: 0.0000201 AC: 3AN: 149556Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 72958
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Palmoplantar keratoderma, Nagashima type Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D;D
GERP RS
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 2
DS_AL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at