rs762427588
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2
The NM_001122752.2(SERPINI1):āc.526A>Gā(p.Thr176Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,574 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 Uncertain significance (ā ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 31)
Exomes š: 0.0000062 ( 0 hom. )
Consequence
SERPINI1
NM_001122752.2 missense
NM_001122752.2 missense
Scores
6
9
3
Clinical Significance
Conservation
PhyloP100: 8.94
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 0 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.984
BS2
?
High AC in GnomAdExome4 at 9 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SERPINI1 | NM_001122752.2 | c.526A>G | p.Thr176Ala | missense_variant | 4/9 | ENST00000446050.7 | |
SERPINI1 | NM_005025.5 | c.526A>G | p.Thr176Ala | missense_variant | 4/9 | ||
SERPINI1 | XM_017006618.3 | c.526A>G | p.Thr176Ala | missense_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SERPINI1 | ENST00000446050.7 | c.526A>G | p.Thr176Ala | missense_variant | 4/9 | 1 | NM_001122752.2 | P1 | |
SERPINI1 | ENST00000295777.9 | c.526A>G | p.Thr176Ala | missense_variant | 4/9 | 1 | P1 | ||
SERPINI1 | ENST00000472747.2 | c.526A>G | p.Thr176Ala | missense_variant | 4/5 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152058Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 251044Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135682
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461516Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727052
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152058Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74276
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 20, 2023 | The c.526A>G (p.T176A) alteration is located in exon 4 (coding exon 3) of the SERPINI1 gene. This alteration results from a A to G substitution at nucleotide position 526, causing the threonine (T) at amino acid position 176 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Familial encephalopathy with neuroserpin inclusion bodies Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 24, 2023 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SERPINI1 protein function. ClinVar contains an entry for this variant (Variation ID: 581921). This variant has not been reported in the literature in individuals affected with SERPINI1-related conditions. This variant is present in population databases (rs762427588, gnomAD 0.002%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 176 of the SERPINI1 protein (p.Thr176Ala). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;T
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Benign
T;T;T
Polyphen
D;D;.
Vest4
MutPred
Loss of glycosylation at T176 (P = 0.1457);Loss of glycosylation at T176 (P = 0.1457);Loss of glycosylation at T176 (P = 0.1457);
MVP
MPC
0.46
ClinPred
D
GERP RS
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gMVP
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