rs1553774731
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_001122752.2(SERPINI1):c.482A>T(p.Asn161Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 31)
Consequence
SERPINI1
NM_001122752.2 missense, splice_region
NM_001122752.2 missense, splice_region
Scores
3
8
7
Splicing: ADA: 0.001002
2
Clinical Significance
Conservation
PhyloP100: 1.02
Genes affected
SERPINI1 (HGNC:8943): (serpin family I member 1) This gene encodes a member of the serpin superfamily of serine proteinase inhibitors. The protein is primarily secreted by axons in the brain, and preferentially reacts with and inhibits tissue-type plasminogen activator. It is thought to play a role in the regulation of axonal growth and the development of synaptic plasticity. Mutations in this gene result in familial encephalopathy with neuroserpin inclusion bodies (FENIB), which is a dominantly inherited form of familial encephalopathy and epilepsy characterized by the accumulation of mutant neuroserpin polymers. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM1
?
In a mutagenesis_site Increases protein stability and abolishes tendency to form polymers. No effect on inhibitory activity. (size 0) in uniprot entity NEUS_HUMAN
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.837
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SERPINI1 | NM_001122752.2 | c.482A>T | p.Asn161Ile | missense_variant, splice_region_variant | 4/9 | ENST00000446050.7 | |
SERPINI1 | NM_005025.5 | c.482A>T | p.Asn161Ile | missense_variant, splice_region_variant | 4/9 | ||
SERPINI1 | XM_017006618.3 | c.482A>T | p.Asn161Ile | missense_variant, splice_region_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SERPINI1 | ENST00000446050.7 | c.482A>T | p.Asn161Ile | missense_variant, splice_region_variant | 4/9 | 1 | NM_001122752.2 | P1 | |
SERPINI1 | ENST00000295777.9 | c.482A>T | p.Asn161Ile | missense_variant, splice_region_variant | 4/9 | 1 | P1 | ||
SERPINI1 | ENST00000472747.2 | c.482A>T | p.Asn161Ile | missense_variant, splice_region_variant | 4/5 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial encephalopathy with neuroserpin inclusion bodies Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2020 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with SERPINI1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with isoleucine at codon 161 of the SERPINI1 protein (p.Asn161Ile). The asparagine residue is moderately conserved and there is a large physicochemical difference between asparagine and isoleucine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
D;D;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
P;P;.
Vest4
MutPred
Loss of ubiquitination at K164 (P = 0.0547);Loss of ubiquitination at K164 (P = 0.0547);Loss of ubiquitination at K164 (P = 0.0547);
MVP
MPC
0.26
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at